Multicenter evaluation of the use of venous thromboembolism prophylaxis in acutely ill medical patients in Canada

BACKGROUND: Venous thromboembolism (VTE) prophylaxis in acutely ill medical patients has been shown to be safe and effective. Underutilization of this patient safety practice may result in avoidable mortality and morbidity. OBJECTIVES: We aimed to determine the proportion of hospitalized, acutely ill medical patients across Canada who were eligible to receive thromboprophylaxis and to evaluate the frequency, determinants and appropriateness of its use. PATIENTS/METHODS: CURVE is a national, multicenter chart audit of 29 Canadian hospitals. Data were collected on consecutive patients admitted to hospital for an acute medical illness during a defined 3-week study period. Information on demographic and clinical characteristics, risk factors for VTE and bleeding and use of VTE prophylaxis were recorded. The indications for and appropriateness of VTE prophylaxis were assessed using pre-specified criteria based on international consensus guidelines. Multivariable analyses were performed to identify determinants of prophylaxis use. RESULTS: Of the 4124 medical admissions screened over the study period, 1894 patients (46%) were eligible for study inclusion. The most common specified admitting diagnoses were severe infection (28%), COPD exacerbation or respiratory failure (12%), malignancy (9%) and congestive heart failure (8%). Thromboprophylaxis was indicated in 1702 (90%) study patients. Overall, some form of prophylaxis was administered to 23% of all patients. However, only 16% received appropriate thromboprophylaxis. Factors independently associated with greater use of prophylaxis included internist (vs. other specialty) as attending physician (OR 1.33, 95% confidence interval (CI) [1.03, 1.71]), university-associated (vs. community) hospital (OR 1.46, 95% CI [1.03, 2.07]), immobilization (per day) (OR 1.60, 95% CI [1.45, 1.77]), presence of >or=1 VTE risk factors (OR=1.78, 95% CI [1.35, 2.34]) and duration of hospitalization (per day of stay) (OR 1.05, 95% CI [1.03, 1.07]), however, use of prophylaxis was unacceptably low in all groups. Patients with cancer had a significantly reduced likelihood of receiving prophylaxis (OR=0.40, 95% CI [0.24, 0.68]). Presence of risk factors for bleeding did not influence the use or choice of prophylaxis. CONCLUSION: Most patients hospitalized for medical illness had indications for thromboprophylaxis, yet only 16% received appropriate prophylaxis. Efforts should be made to elucidate the reasons that underlie the very low rate of thromboprophylaxis in medical patients and to develop and test strategies to improve implementation of this patient safety practice.     

Sulfated low molecular weight lignins,allosteric inhibitors of coagulation proteinases via the heparin binding site,significantly alter the active site of thrombin and factor xa compared to heparin

Sulfated low molecular weight lignins (LMWLs) have been found to bind in the heparin binding sites of coagulation proteinases. LMWLs represent a library of diverse non-carbohydrate, aromatic molecules which are structures different from heparin, but still potently inhibit thrombin and factor Xa. To better understand their mechanism of action, we studied the effects of three sulfated LMWLs (CDSO3, FDSO3, and SDSO3) on the active sites of thrombin and factor Xa. LMWLs were found to uniformly inhibit the catalytic activity of thrombin and factor Xa, regardless of the substrate used. Michaelis-Menten kinetic studies indicate that maximal velocity of hydrolysis of each chromogenic substrate decreases significantly in the presence of sulfated LMWLs, while the effect on Michaelis constant is dependent on the nature of the substrate. These studies indicate that LMWLs inhibit thrombin and factor Xa through allosteric disruption of the catalytic apparatus, specifically through the catalytic step. As opposed to heparin, LMWLs significantly alter the binding of the active site fluorescent ligand p-aminobenzamidine. LMWLs also had a greater effect on the molecular orientation of fluorescein-labeled His 57 than heparin. The molecular geometry surrounding the most important catalytic amino acid, Ser 195, was significantly altered by the binding of LMWLs while heparin had no measurable effect on Ser 195. These results further advance the concept of sulfated LMWLs as heparin mimics and will aid the design of anticoagulants based on their novel scaffold.     

Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux in different clinical settings

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies that recognize platelet factor 4 (PF4)/heparin complexes. The frequency of HIT is highly variable in different clinical settings, and is more frequent with unfractionated heparin (UFH) than with low-molecular-weight heparin (LMWH), despite the in vitro observation that HIT antibodies activate platelets similarly well with LMWH as with UFH. An important difference between UFH, LMWH, and fondaparinux is their widely differing plasma concentrations. We aimed to provide a model that included anticoagulant concentrations and PF4 availability as risk factors influencing the anti-PF4/heparin immune response. MATERIALS AND METHODS: By photon correlation spectroscopy we determined the concentrations at which UFH, LMWH, and fondaparinux form complexes optimally with PF4. Plasma concentrations of UFH and LMWH were calculated based on ex vivo pharmacokinetic data, with information on fondaparinux and PF4 concentrations taken from the literature. RESULTS AND CONCLUSIONS: The main features of our model are: optimal complex formation occurs at prophylactic-dose UFH and high PF4 levels, whereas therapeutic-dose LMWH concentrations are too high for optimal complex formation; in contrast, concentrations of fondaparinux are usually below the optimal stoichiometric range. Thus, immunization should occur more often in situations with major rather than minor platelet activation, and--for a given degree of platelet activation (PF4 availability)--as: prophylactic-dose UFH>therapeutic-dose UFH>prophylactic-dose LMWH, fondaparinux>therapeutic-dose LMWH. Our model provides a framework for explaining empirical observations that LMWH induces less anti-PF4/heparin antibodies than does UFH, and that anti-PF4/heparin antibodies are more often found in patients undergoing major surgery than in medical patients.     

Direct comparison of enoxaparin and nadroparin in a rabbit model of arterial thrombosis prevention

Introduction

The aim of the study was to evaluate and compare the efficacy of standard unfractionated heparin (UFH) and low-molecular weight heparins (LMWH's).

Materials and Methods

We modified a previously published rabbit model of arterial thrombosis prevention [1,2] to compare unfractionated heparin and two different doses of two low-molecular weight heparin fragments - nadroparin and enoxaparin. Thrombosis in the distal aorta was triggered by vessel wall injury and critical stenosis. Blood flow in the damaged arterial segment was monitored by a flow probe placed distal to the constrictor. The primary endpoints of the study were: (1) cumulative flow, (2) time to occlusion and (3) residual clot weight. Thirty six animals were split into 6 groups with six animals in each group. Control groups were given saline or heparin and four more groups were used to compare LMWH's at 2 different doses.

Results

In our study, all treatments were superior to the saline control group (α ≤ 0,01). Standard heparin was inferior (α ≤ 0,05) to both low molecular weight heparins for all primary endpoints (cumulative flow, time to occlusion and residual clot weight). There were no differences between the LMWH's except for cumulative flow at high doses.

Conclusions

This study revealed no relevant differences between nadroparin and enoxaparin for the primary endpoints of our model. Clinical use of each drug remains a personal preference.     

Inter-individual variability of effect of 7 low molecular weight antithrombin-dependent anticoagulants studied in vitro with Calibrated Automated Thrombography

Introduction

Low-molecular-weight heparins (LMWHs) and fondaparinux are antithrombin dependent anticoagulant drugs considered to need no laboratory monitoring because of their reputedly predictable anticoagulant effect. However it has been suggested in the literature the existence of an inter-individual variability in response to LMWHs that would be not fully attributable to pharmacokinetics causes.

Material and methods

In order to separate pharmacokinetic from pharmacodynamics effects we studied in 12 platelet-depleted plasmas from normal donors the inhibitory effect on TG determined with the CAT of added UFH, 5 LMWHs and 2 oligosaccharides with anti-Xa activity only.

Results

A concentration-dependent inhibition of thrombin generation was found with all molecules tested. The concentration-response relation was very different when the concentrations were expressed in anti-Xa unit but became very similar when expressed in anti-thrombin units regarding LMWHs. Most importantly, we noticed a large inter-individual variability of the inhibitory effects with all molecules tested, UFH and LMWHs alike. The IC40 value varied at least twofold between the highest and the lowest responder. For any given anti-Xa level of any heparin and of pentasaccharide the inhibition of the ETP showed scattering of around 25%.

Conclusion

In contrast to what is generally assumed the inter-individual variation of the in vitro pharmacodynamics response is equally high for UFH and any LMWH (~ 25%) and even for the synthetic pentasaccharide. This questions the rationale for standard dosage, the more so as in clinical practice pharmacokinetic variation (e.g. due to body weight) will add to this pharmacodynamic variability.     

Antiangiogenic activities of bemiparin sodium, enoxaparin sodium, nadroparin calcium and tinzaparin sodium

Introduction

The low-molecular-weight heparins have been demonstrated to have antiangiogenic effects in various assays. We aimed to demonstrate and compare the antiangiogenic effects of four types of commercially available low-molecular weight heparins in the chick embryo chorioallantoic membrane model.

Materials and methods

The antiangiogenic efficacies of bemiparin, enoxaparin, nadroparin, and tinzaparin were examined in vivo in the chick chorioallantoic membrane model. Drug solutions are prepared in three different concentrations (100 IU, 10 IU, or 1 IU/10 μl). For each set of experiment twenty fertilized eggs were used. The decrease of vessel formation is examined and scored according to previous literature.

Results

Bemiparin, enoxaparin, nadroparin, and tinzaparin sodium all have antiangiogenic effects on chick chorioallantoic membrane at the concentration of 100 IU/10 μl. This effect was also observed in 10 IU/10 μl concentrations of nadroparin and tinzaparin.

Conclusions

The low molecular weight heparins studied have obvious antiangiogenic effects. There may be a difference in the potency of the drugs that could have a significant implication for further clinical research.     

Postpartum wound and bleeding complications in women who received peripartum anticoagulation

Introduction

The objective of this study was to compare wound and bleeding complications between women who received anticoagulation after cesarean delivery due to history of prior venous thromboembolic disease, arterial disease, or being a thrombophilia carrier with adverse pregnancy outcome, to women not receiving anticoagulation.

Methods

Women in the Duke Thrombosis Center Registry who underwent cesarean delivery during 2003-2011 and received postpartum anticoagulation (anticoagulation group, n = 77), were compared with a subset of women who delivered during the same time period, but did not receive anticoagulation (no anticoagulation group, n = 77). The no anticoagulation group comprised women who were matched to the anticoagulation group by age, body mass index, type of cesarean (no labor vs. labor), and date of delivery. Bleeding and wound complications were compared between the two groups. A multivariable logistic regression model was constructed to determine if anticoagulation was an independent predictor of wound complication.

Results

Women who received anticoagulation during pregnancy had a greater incidence of wound complications compared to those who did not (30% vs. 8%, p < 0.001). Using multivariable logistic regression, while controlling for race, diabetes, chorioamnionitis, and aspirin use, anticoagulation predicted the development of any wound complication (OR 5.8, 95% CI 2.2, 17.6), but there were no differences in the mean estimated blood loss at delivery (782 vs. 778 ml, p = 0.91), change in postpartum hematocrit (5.4 vs. 5.2%, p = 0.772), or percent of women receiving blood products (6.5 vs. 1.3%, p = 0.209) between the two groups.

Conclusions

Anticoagulation following cesarean delivery is associated with an increased risk of post-cesarean wound complications, but not other postpartum bleeding complications.     

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.     

Purification, characterization and in vivo studies of salmon heparin

Heparin was purified from gills and intestines from farmed Atlantic salmon (Salmo salar).Heparin activity was determined after size exclusion chromatography in the molecular weight range from above 8,000 to near 1,500. A specific activity of 110.1 antifactor Xa units/mg was measured in the less than 3,500 molecular weight fraction while 136.8 antifactor Xa units/mg was detected in a 8,000-3,500 molecular weight fraction.The presence of high affinity salmon heparin was demonstrated by using chromatography on antithrombin-Sepharose. Heparin with molecular weights lower than 3,500 was found both in high and low affinity fractions. NMR-analysis detected N- and O-sulfated oligosaccharides essential for heparin activity.The amount of salmon heparin with molecular weight lower than 8,000 varied from 12% to almost 100%. The factors determining this variation is not known, but appears to reside in the fish at the time of slaughter.The in vivo effect of salmon heparin was tested in rabbits using dalteparin as control. Salmon heparin activity was recovered in plasma samples expressed as antifactor Xa activity after intravenous administration. Based on a small number of samples and animals, the results indicate that in vivo half-life time of salmon heparin was higher than that of dalteparin.     

French clinical practice guidelines on the management of patients on vitamin K antagonists in at-risk situations (overdose, risk of bleeding, and active bleeding)

The present report from several French medical societies in the field and the French National Authority for Health provides an expert consensus for the management of patients on vitamin K antagonists in at-risk situations (overdose, risk of bleeding, and active bleeding). Asymptomatic VKA overdose is defined as an International Normalized Ratio (INR) value above the upper limit of the therapeutic target. In this case, the guidelines describe the rapid reduction of the INR down to the therapeutic range, either by omitting a dose or using vitamin K. Regarding the haemorrhagic complications, the guidelines address the management of these patients according to the severity of bleeding, and especially focus on the use of prothrombin complex concentrate. Finally, the consensus addresses the management of patients in cases of elective or emergency surgery or other invasive procedures, and discusses whether treatment should be continued or not, and whether VKA substitution by heparin - “bridging anticoagulation” - is needed.     

A new plastic collection tube made of polyethylene terephtalate is suitable for monitoring traditional anticoagulant therapy (oral anticoagulant, unfractionated heparin, and low molecular weight heparin)

To improve the safety of blood collection, plastic tubes have been developed but various interactions with the coagulation system and/or antithrombotic drugs were reported with the first generation of such tubes. The aim of this multicentre study was to compare hemostasis test results measured in evacuated plastic tubes made of polyethylene terephtalate (VenoSafe, Terumo Europe) and in siliconized glass tubes containing the same citrate concentration (0.129 M). In addition, the impact of aging of the plastic tube was investigated by collecting blood samples in tubes at 8 months and at 1 month before expiry. Blood was drawn in 3 centres from untreated patients (n=269), patients on oral anticoagulant treatment (OAT, n=221), and patients treated with either unfractionated heparin (UFH, n=73) or a low molecular weight derivative (LMWH, n=48). Prothrombin time (PT) or INR, activated partial thromboplastin time (APTT) and anti-FXa activity were locally performed, when applicable. In untreated patients and in patients on OAT, PT and APTT values were found statistically shorter (p<0.05) when evaluated in plastic tubes than in glass tubes, except when PT was evaluated using a human thromboplastin. Surprisingly, significantly longer APTT and higher anti-FXa activities were obtained when blood from patients on UFH was drawn in plastic than in glass tubes. However, none of the differences had any clinical relevance (Bland-Altman analysis). In patients on anticoagulant treatment, there was no effect of aging of the plastic tubes. These results suggest that the plastic tube VenoSafe is suitable for coagulation testing both in untreated subjects and more interestingly in patients on traditional anticoagulant therapy during the whole shelf life indicated by the manufacturer.     

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.     

Increased heparanase level and procoagulant activity in orthopedic surgery patients receiving prophylactic dose of enoxaparin

Background

Orthopedic hip and knee surgeries are followed by a hypercoagulable state. Heparanase is implicated in inflammation, coagulation activation and angiogenesis. Recently, heparanase was shown to directly interact with tissue factor (TF) and to enhance the generation of factor Xa (Nadir et al., Haematologica, 2010). In addition, an assay assessing heparanase procoagulant activity has been lately developed (Nadir et al., Thromb Res, 2011). In the present study heparanase level and procoagulant activity in patients undergoing orthopedic surgery were assessed.

Methods

The study group included 50 orthopedic patients. 31 patients underwent hip surgery and 19 had knee operation. 15 individuals suffered from traumatic hip fractures and 35 had osteoarthrosis of hip or knee joints. All patients received prophylactic dose of enoxaparin starting 6-8 hours post operation and lasting for 5 weeks. Plasma samples were drawn preoperatively and at 1 hour, 1 week and 1 month post operation. Samples were tested for heparanase levels by ELISA and TF/heparanase complex activity, TF activity, heparanase procoagulant activity, factor Xa and thrombin levels using chromogenic substrates.

Results

Heparanase levels were significantly higher 1 hour and 1 week post operatively compared to preoperative levels (p < 0.05, p < 0.005, respectively). The most dramatic changes were observed in heparanase procoagulant activity reaching a 2 fold increase 1 week postoperatively and 1.7 fold increase 1 month after surgery (p < 0.0001, p < 0.0001, respectively). Levels of factor Xa and thrombin did not significantly change.

Conclusions

Heparanase is involved in coagulation activation of orthopedic surgery patients. Heparanase procoagulant activity is highest 1 week postoperatively and remains high 1 month after operation. Considering extending prophylactic anticoagulant therapy or evaluating heparanase procoagulant activity may potentially prevent late thrombotic events.     

Low-molecular-weight heparin inhibition in classical complement activaton pathway during pregnancy

Introduction

Low-molecular-weight heparin is used clinically for the prevention of pregnancy complications associated with prothrombotic disorders, particularly anti-phospholipid syndrome. Nevertheless, recent studies have suggested that heparin may exert direct effects on the placental trophoblast, independently of its anticoagulant activity. In addition, heparin prevents complement activation in vivo and protects mice from pregnancy complications.

Materials and Methods

The inhibition of the classical complement activation pathway by heparin was analyzed by means of in vitro assays and in pregnant women receiving prophylaxis with therapeutic doses (40 mg/day) of subcutaneous low molecular weight heparin by haemolysis of antibody-sensitized sheep erythrocytes (CH₅₀ assay).

Results

The specific interaction between low-molecular-weight heparin and the C1q subunit of the C1 complex of the complement cascade allowed the isolation of a small subpopulation of heparin ( 8.03 ± 1.20 μg %), with an anti-activated factor X activity more than four times greater than the starting material. This subpopulation could be responsible for the in vitro inhibition of the classical complement activation pathway evaluated by the total haemolysis of antibody-sensitized sheep erythrocytes. About 60 µg/ml of low molecular weight heparin was needed to achieve 50% of haemolysis. The detection of the classical complement pathway inhibition in pregnant women treated with heparin required a first activation with aggregated human IgG.

Conclusions

We concluded that the interaction between low-molecular-weight heparin and C1q could be relevant not only in the complement-dependent, but also in the complement-independent inflammation mechanisms responsible for the prevention of pregnancy loss.     

Incidence and risk factors for developing venous thromboembolism in Japanese with diffuse large b-cell lymphoma

The reported incidence of venous thromboembolism (VTE) in lymphoma patients is 5% to 17% in Western countries. The incidence and risk factors for developing VTE, however, are not well elucidated in Asian lymphoma patients. The incidence and clinical presentations of VTE were retrospectively assessed in 142 patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL) from April 2006 to November 2010 at Keio University Hospital. Clinical data were collected and all episodes of symptomatic VTE confirmed by imaging were included. Patients with primary central nervous system lymphoma or DLBCL transformed from prior low-grade lymphoma were excluded. Fifteen (11%) patients had at least one episode of VTE. Five patients developed VTE before beginning chemotherapy and 8 episodes of VTE occurred during the first three cycles of chemotherapy. By univariate analysis, age 60 or over (odds ratio [OR] 4.81, confidence interval [CI] 1.04-22.20, p = 0.04), Eastern Cooperative Oncology Group performance status 2, 3, or 4 (OR 39.90, CI 5.05-315.20, p = 0.0005), and International Prognostic Index high or high-intermediate (OR 9.40, CI 1.20-73.69, p = 0.03) were identified as risk factors for developing VTE. By multivariate analysis, performance status 2, 3, or 4 remained a significant risk factor for developing VTE (OR 31.14, CI 3.79-255.62, p = 0.001). The incidence of VTE in Japanese with DLBCL was comparable with that in the Western population. Patients with DLBCL and poor performance status at diagnosis were at high risk for developing VTE especially early in the course of treatment.     

Use of the Delphi method to facilitate antithrombotics prescription during pregnancy

Introduction

Management of pregnant women at risk for venous thromboembolism (VTE) remains complex. Guidelines do not definitively fix optimal strategies due to limited trial data. Our objective was to build an easy-to-use tool allowing individualised, risk-adapted prophylaxis.

Materials and Methods

A Delphi exercise was conducted to collect 19 French experts’ opinions on pregnancy-related VTE.

Results

Experts with an active interest in clinical research and care of VTE and placental vascular complications were selected. The risk score was classified by an anonymous computer vote. A scoring system for VTE risk in pregnant women was developed, each score being associated with a specific treatment: graduated elastic compression stockings, aspirin, prophylactic Low Molecular Weight Heparin (LMWH: variable durations), or adjusted-dose of LMWH through pregnancy and postpartum.

Conclusions

Our simple consensual scoring system offers an individual estimation of thrombosis risk during pregnancy together with its related therapeutic strategy, in accordance with most of the new international recommendations. The accuracy of our individual risk score-based therapeutic guidance is currently being prospectively evaluated in a multicenter trial (Clinicaltrials.gov registry no: NCT00745212).     

Insight into the profibrinolytic activity of dermatan sulfate: effects on the activation of plasminogen mediated by tissue and urinary plasminogen activators

INTRODUCTION: Dermatan sulfate (DS) is well-known for its anticoagulant activity through binding to heparin cofactor II to enhance antithrombin action. It has also been suggested that DS has a profibrinolytic effect, although the exact molecular mechanism is as yet unknown. MATERIALS AND METHODS: An in vitro amidolytic method was used to study the effect of high and low molecular weight-DS on the activation of Glu and Lys-plasminogen by tissue and urinary plasminogen activators (t-PA and u-PA). RESULTS: Both high and low molecular weight-DS exhibited a stimulating effect on the activation of plasminogen by PAs. Interestingly, high molecular weight-DS stimulated Glu and Lys-plasminogen activation by t-PA and u-PA in a way and to an extent similar to that in which fibrin(ogen) degradation products (PDF) increased the t-PA assay. Meanwhile low molecular weight-DS had a lower effect. No DS had any effect on plasmin or u-PA amidolytic activity. The facilitation of the conversion of Glu-plasminogen to plasmin in the presence of DS was confirmed by SDS-PAGE; high molecular weight-DS effect was greater than low molecular weight-DS in accordance with the chromogenic assays. Moreover, the combination of PDF and high and low molecular weight-DS, respectively, did not further stimulate t-PA activation of either Glu or Lys-plasminogen suggesting that both substances may compete for the same binding sites. CONCLUSIONS: Through in vitro assays we demonstrated that high and low molecular weight-DS enhance plasminogen activation by u-PA and t-PA, suggesting that the profibrinolytic activity of DS might be via potentiation of plasminogen conversion to plasmin.     

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.     

Incidence and characteristics of asymptomatic distal deep vein thrombosis unexpectedly found at admission in an Internal Medicine setting

Introduction

Lower limb deep vein thrombosis (DVT) is the most frequent clinical manifestation of venous thromboembolism (VTE) and can involve proximal or distal veins. Distal DVT (dDVT) is often asymptomatic and data about its incidence and prognosis are scanty, especially in high risk medical inpatients. Therefore, no consensus exists on the value of detecting and treating dDVTs. Aim of study was to evaluate incidence and characteristics of asymptomatic isolated dDVT at admission in an Internal Medicine department.

Materials and methods

Consecutive patients hospitalized for acute medical illnesses, in whom VTE was not the admission diagnosis, underwent Doppler Ultrasonography. For all patients with dDVT standard treatment with therapeutic doses of low molecular weight heparin or fondaparinux was proposed. Follow-up visits were scheduled at 1, 6 and 12 weeks.

Results

One-hundred-fifty-four patients were enrolled. In 4.5% a proximal DVT and in 16.2% an asymptomatic dDVT were found. Female sex, elevated age and renal and electrolyte abnormalities were significantly associated to dDVT (p = 0.014, p = 0.009 and p = 0.046, respectively). Only low degree of mobility (LDM) was independently associated to dDVT [OR 7.97 (95%CI 2.42-26.27), p = 0.001)]. A high mortality rate, not for VTE-related causes, was found, especially in the first week, among dDVT patients.

Conclusions

We found a high incidence of clinically silent dDVTs. LDM evaluation could be useful to select patients at high risk in whom to perform a search for dDVT.