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.     

Subcutaneous Enoxaparin for Therapeutic Anticoagulation in Hemodialysis Patients

Background

Information regarding dosing of low-molecular-weight heparins (LMWH) for therapeutic anticoagulation in hemodialysis (HD) patients is limited. The aim of this study was to retrospectively compare the safety and efficacy of enoxaparin versus unfractionated heparin (UFH) for therapeutic anticoagulation in HD patients.

Materials and Methods

This retrospective chart review evaluated HD patients treated with subcutaneous enoxaparin that were matched based on the indication for anticoagulation with patients treated with intravenous UFH to achieve therapeutic anticoagulation. Primary outcome measures included 30-day incidence of thromboembolic events and major bleeding. Secondary outcomes included rehospitalization within 30 days, length of stay, and mortality.

Results

One hundred sixty-four patients were evaluated, 82 in each group. The average daily dose of enoxaparin used to target therapeutic levels was 0.7 ± 0.2 mg/kg/day (range = 0.4-1). Comparing enoxaparin to UFH, there was no significant difference in major bleeding (6.1% vs 11%, p = 0.4) or thromboembolism (0% vs 2.4%, p = 0.5). Hospital length of stay was shorter in the enoxaparin group (20 ± 53.8 vs 28.9 ± 44.5 days, p = 0.02); there was no significant difference between groups in mortality or readmission. Adjusting for risk factors for bleeding there was a slight but statistically non-significant difference between enoxaparin versus UFH (OR = 0.77, 95%CI: 0.2-3.5, p = 0.73).

Conclusions

These findings suggest that therapeutic dosing of enoxaparin, in doses that ranged from 0.4-1 mg/kg/day, was as safe as intravenous UFH in providing therapeutic anticoagulation in stable patients requiring chronic hemodialysis.     

Circulating platelet-derived microparticles and endothelium-derived microparticles may be a potential cause of microthrombosis in patients with osteonecrosis of the femoral head

Introduction

To test the hypothesis that the platelet microparticle (PMP) and endothelial microparticle (EMP) may contribute to the hypercoagulability associated with microvascular thrombosis in patients with nontraumatc osteonecrosis of the femoral head (ONFH).

Materials and methods

The study comprised 46 patients who had been diagnosed with ONFH and 20 control subjects. The plasma was ultracentrifuged, and then PMPs and EMPs were examined by the flow cytometry. The thrombotic and fibrinolytic disorders were investigated.

Results

The numbers of PMPs expressing P-selectin and CD42a and EMPs expressing E-selectin and CD31 in the ONFH patients were significantly higher than those in the controls (P < 0.001). The number of MPs was correlated with the level of the serum C-reactive protein (CRP) (r = 0.661, P < 0.001), but there was a poor correlation between the MPs counts and the risk factors for ONFH (P > 0.05). The mean levels PAI-1, F1 + 2, and TAT were higher in the patients with ONFH than in the controls (P < 0.05).

Conclusions

The elevated numbers of PMPs and EMPs may contribute to hypercoagulability in the ONFH patients. This may provide important pathophysiological insights into the hypercoagulability associated with nontraumatic ONFH and have implications for pharmacological prevention and treatment of ONFH.     

Tissue factor-induced Thrombin Generation in the Fasting and Postprandial State among Elderly Survivors of Myocardial Infarction

Introduction

Tissue factor (TF)-induced thrombin generation (TG) ex vivo has been suggested to be an important method to assess thrombotic risk. No studies have investigated the impact of postprandial lipemia on TF-induced TG. Since myocardial infarction (MI) is associated with elevated postprandial levels of triglycerides, we hypothesized a differential impact of postprandial lipemia on coagulation activation in MI-patients and healthy controls.

Material and Methods

Elderly survivors of acute MI (n = 44) and healthy age-and sex matched controls (n = 43) underwent a fat tolerance test (1 gram per kg body weight) to assess coagulation activation during postprandial lipemia.

Results

The incremental area under the curve (AUCi) for serum triglycerides was higher in MI-patients than in healthy age-and sex matched controls (5.64 ± 0.52 mmol/L?h and 3.94 ± 0.39 mmol/L?h, p = 0.012) during the postprandial phase. Subsequent endogenous activation of coagulation, assessed by FVIIa and thrombin generation (F1 + 2), was similar among groups and not related to levels of triglycerides during the postprandial phase. Healthy individuals had a gradual decline in TF-induced thrombin generation ex vivo, assessed by endogenous thrombin potential (ETP) (AUCi = - 542.4 ± 71.4 nM?min?h, p < 0.001), whereas MI-patients retained their ETP (AUCi = 127.4 ± 89.0 nM?min?h, p = 0.47) in plasma during the postprandial phase (p for group difference = 0.005).

Conclusions

MI-patients had elevated postprandial lipemia and retained their ability for TF-induced TG in plasma ex vivo in the postprandial phase, whereas the capacity gradually decreased in healthy individuals. Further studies are warranted to reveal underlying mechanism(s) and clinical implications.     

Activation of coagulation in amniotic fluid during normal human pregnancy

Introduction

Amniotic fluid (AF) is an important medium for fetal development which exhibits high procoagulant activities; however, the role of these procoagulants during pregnancy has not been elucidated and might be associated with pregnancy complications. The current study aimed to evaluate factor X (FX) activation and its association with tissue factor (TF), tissue factor pathway inhibitor (TFPI) and coagulation activation markers in AF during normal human pregnancy.

Methods

Activation of FX and concentration of TF, free TFPI, D-dimer and prothrombin fragments (F1 + 2) were evaluated in AF samples obtained for chromosome analysis from 91 women with normal pregnancy: 65 samples were taken from patients at 16-20 weeks of gestation, 9 samples were drawn at 21-30 weeks and 17 samples−after 30 weeks of gestation.

Results

Activation of FX in AF significantly increased during normal pregnancy (from 65 ± 41 to 205 ± 80 equivalent RVV ng/mg total protein, P < 0.0001). TF and TFPI levels in AF also rose with gestational age. In contrast, the AF concentration of D-dimer and F1 + 2, markers of coagulation activation significantly decreased when expressed per mg total protein. Levels of free TFPI correlated with TF (r = 0.5, P < 0.001), and were 8-fold higher than those of TF during pregnancy.

Conclusion

High levels of TFPI might be associated with the inhibition of procoagulant activity in amniotic fluid during normal pregnancy, which may account for the rarity of clinical amniotic fluid embolism.     

Analysis of unfractionated heparin dose requirements to target therapeutic anti-Xa intensity during pregnancy

Introduction

Unfractionated heparin (UFH) does not cross the placenta and has demonstrated utility in the prevention and treatment of thrombosis during pregnancy. Limited information is available to guide initiation and monitoring of therapeutic UFH targeting an anti-Xa concentration of 0.3-0.7 u/ml during pregnancy. The objective of this study was to describe UFH doses and monitoring strategies required to achieve and maintain therapeutic anti-Xa intensity in a cohort of women treated with UFH during pregnancy.

Materials/Methods

Patients prescribed anti-Xa adjusted UFH during pregnancies occurring between January 1998 and March 2005 were included.

Results

A total of 39 pregnancies for 37 women were identified. Unfractionated heparin doses were titrated to achieve a mid-interval anti-Xa level of 0.3-0.7 u/ml. Patients required a median 6.5 days and a mean UFH dose of 403.5 u/kg/day to achieve therapeutic anti-Xa levels. Most anti-Xa levels were within the target range (59%). The final UFH dose/kg required at the end of pregnancy was similar to that at the first therapeutic level (P > 0.05); however some patients did require dose modification. Patients required a mean 14.1 anti-Xa determinations and 4.6 dose modifications during a mean 23.9 weeks of antenatal UFH therapy. Patient weight and UFH dose at the first therapeutic anti-Xa level were correlated (r = 0.383, P = 0.018).

Conclusions

Pregnant women required a mean UFH dose of 403.5 u/kg/day to achieve midinterval anti-Xa levels of 0.3-0.7 u/ml. The required dose was correlated with patient weight and most anti-Xa measurements were within the target range.     

In vitro comparison of dabigatran, unfractionated heparin, and low-molecular-weight heparin in preventing thrombus formation on mechanical heart valves

Introduction

Lifelong oral anticoagulation (OAC) therapy is required for the prevention of thromboembolic events after implantation of an artificial heart valve. Thromboembolism and anticoagulant-related bleedings account for ≈ 75% of all complications experienced by heart valve recipients (2-9% of patients per year). The present study investigated the efficacy of dabigatran, a new direct thrombin inhibitor for oral use, as compared to unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in preventing thrombus formation on mechanical heart valves in vitro.

Material and Methods

Blood (230 ml) from healthy young male volunteers was anticoagulated either by dabigatran (1 μmol/l), UFH (150 IU), or LMWH (100 IU). Mechanical heart valve prostheses were placed in an in vitro thrombosis tester and exposed to the anticoagulated blood samples under continuous circulation at a rate of 75 beats per minute.

Results

In whole blood with no anticoagulant, the apparatus completely clotted in 15-20 minutes. When blood was treated with dabigatran, the mean thrombus weight was 164 ± 55 mg, in the UFH group 159 ± 69 mg, and in the LMWH group 182 ± 82 mg (p-value: 0.704). Electron microscopy showed no significant difference in thrombus formation in any group.

Conclusisons

Dabigatran was as effective as UFH and LMWH in preventing thrombus formation on mechanical heart valves in our in vitro investigation. Thus, we hypothesize that dabigatran etexilate might potentially be a useful and competitive orally administered alternative to UFH and LMWH for recipients of alloplastic heart valve prostheses.     

Interleukin-10 promoter microsatellite polymorphisms influence the immune response to heparin and the risk of heparin-induced thrombocytopenia

Introduction

Heparin-induced thrombocytopenia (HIT) results from an atypical immune response with synthesis of IgG antibodies (Abs) to platelet factor 4/heparin complexes (PF4/H), and probably involves both B and T cells. We investigated whether 3 single nucleotide polymorphisms (SNPs), rs1800896 (− 1082G/A), rs1800871 (− 819C/T) and rs1800872 (− 592C/A) and the polymorphic CA repeat microsatellites IL10R [5325CA(11_15)] and IL10G [8134CA(14_29)] are associated with the synthesis of Abs to PF4/heparin and HIT.

Materials and methods

Eighty-two patients with definite HIT and two control groups were studied. The first control group (Ab^neg) consisted of 85 patients without Abs to PF4/heparin after cardiopulmonary bypass (CPB). The second control group (Ab^pos) consisted of 84 patients who had developed significant levels of PF4-specific antibodies after CPB, but without HIT.

Results

Allele frequencies of the 3 SNPs were similar in HIT patients and controls. Fourteen alleles in IL10G (G16 to G29) and 3 alleles in IL10R (R13 to R15) were defined. The short G20 allele of IL10G was more frequent in Ab^neg patients (8.2%) than in Ab^pos (2.9%) and HIT patients (3%). It thereby appeared to protect against developing Abs to PF4/heparin (OR 0.29; 95% CI [0.12-0.70], p = 0.006). Combined haplotypes cH1/cH8 comprising the short G20 + R13 alleles were less frequent in HIT (OR 0.33; 95% CI [0.11-0.97], p = 0.036), and levels of Abs to PF4 in Ab^pos patients were lower in cH1/cH8 subjects (p = 0.019).

Conclusion

These results suggest that IL10 promoter microsatellite polymorphisms might influence the immune response against PF4/heparin and the risk of HIT.     

P-selectin/ PSGL-1 Inhibitors versus enoxaparin in the resolution of venous thrombosis: A meta-analysis

Background

P-selectin antagonism has been shown to decrease thrombogenesis and inflammation in animal models of deep venous thrombosis (DVT).

Objective

To determine the effectiveness of P-selectin inhibitors versus saline and enoxaparin in venous thrombus resolution in nonhuman primate models of venous thrombosis.

Methods

Studies reporting vein re-opening, inflammation expressed as Gadolinium enhancement and coagulation parameters were searched in the literature and pooled into a meta-analysis using an inverse variance with random effects.

Results

Five studies were identified comparing P-selectin/ PSGL-1 inhibitors versus saline or enoxaparin regarding venous thrombosis resolution. Vein re-opening was significantly higher on P-selectin/ PSGL-1 compounds, when compared to saline (Inverse Variance [IV] 95% CI; 44.37 [17.77^_70.96], p = 0.001, I² = 97%) and similar to enoxaparin (IV 95% CI; 5.03 [-8.88^_18.95], p = 0.48, I² = 41%). Inflammation, reflected as Gadolinium enhancement at magnetic resonance venography (MRV), was significantly decreased in the P-selectin treated group when compared to saline (IV 95% CI; -17.84 [-14.98 ^_ -8.30], p < 0.00001, I² = 80%). No significant differences on vein wall inflammation were observed between P-selectin/ PSGL-1 inhibitors and enoxaparin treated animals (IV95% CI; -3.59 [-10.67^_3.48], p = 0.32, I² = 66%). In addition, there was no differences in the coagulation parameters (aPTT, TCT, BT, D-Dimer, fibrinogen, platelets) between P-selectin/ PSGL-1 inhibitors and enoxaparin (IV 95% CI; -1.12[-2.36^_0.11], p = 0.07, I² = 92%), although there was a trend showing less of a prolongation in TCT with P-selectin/PSGL-1 inhibitors compared to enoxaparin (p < 0.0001).

Conclusion

P-selectin antagonism successfully paralleled the low-molecular-weight-heparin enoxaparin, for the treatment of DVT in nonhuman primate models, by decreasing both thrombus burden and inflammation without causing any bleeding complications and without increasing coagulation times.     

oxLDL – the molecule linking hypercoagulability with the presence of cardiovascular disease in hemodialyzed uraemic patients

Introduction

Patients with end-stage renal disease (ESRD) exhibit features of a hypercoagulable state, which may contribute to cardiovascular complications. Data from “in vitro” studies suggest that cell-free plasma lipids and lipoproteins may be capable to support thrombin generation. The aim of this study has been to establish the role of plasma oxidized LDL (oxLDL) in the coagulation activation in hemodialyzed (HD) patients with and without cardiovascular disease (CVD).

Materials and Methods

We examined relationship between a marker of coagulation activation – prothrombin fragments 1 + 2 (F_1 + 2), and plasma oxLDL levels in 60 HD patients with and without CVD and in 20 healthy controls.

Results

F_1 + 2 levels were significantly higher in HD patients than in controls, and they were higher in HD patients with CVD compared to those without CVD (p < 0.001). Conversely, oxLDL levels were similar in HD patients with CVD and healthy controls, whereas this parameter was lower in HD patients without CVD when compared to controls and patients with CVD (both p < 0.01). Close positive and independent association was between F_1 + 2 and oxLDL levels in HD patients. Nitrates treatment and the presence of pyelonephritis were associated with reduced oxLDL as well as hypercoagulability in HD patients with cardiovascular complications.

Conclusion

This study demonstrates the independent association between oxLDL and the marker of coagulation activation - F_1 + 2 in HD patients. This new observation may offer a better understanding of the complex mechanism leading to hypercoagulability, which is markedly intensified in these patients, particularly in those with CVD.     

Effects of the etonogestrel-releasing contraceptive implant inserted immediately postpartum on maternal hemostasis: A randomized controlled trial

Introduction

The puerperium is the period of highest risk for thrombosis during a woman´s reproductive life and it is an important time for initiating an effective contraceptive method in order to increase intergestational interval. Thus, the objective of the present study was to evaluated the effects of the etonogestrel (ENG)-releasing contraceptive implant inserted immediately postpartum on maternal hemostasis markers during the first six weeks of delivery.

Materials and Methods

Forty healthy women aged 18 to 35 years-old were randomized to receive either the ENG-releasing implant 24-48 h after delivery (implant group; n = 20) or nothing (control group) until the sixth postpartum week. Blood samples were collected at 24-48 h and at 6 weeks after delivery, and hemostatic variables, including fibrinogen, coagulation factors, protein C, free protein S, antithrombin, α2-antiplasmin, plasminogen activator inhibitor 1, thrombin-antithrombin complex (TAT), prothrombin fragment (PF)1 + 2, and D-dimers, as well as normalized activated protein C sensitivity ratio (nAPCsr), thrombin time, activated partial thromboplastin time, and prothrombin time were evaluated.

Results

Insertion of the ENG-releasing contraceptive implant did not change the physiological reduction in overall coagulation (TAT and PF1 + 2) and fibrinolysis (D-dimer) markers, or nAPCsr. Reductions in factors II, VII, X and fibrinogen and increases in factor V were greater in the control than in the implant group. Clotting factors remained within normal limits throughout the study.

Conclusion

The ENG-releasing contraceptive implant inserted immediately postpartum did not have negative effects on physiological variations of the hemostatic system during the first 6 weeks postpartum.     

Prothrombin fragment 1 + 2 in urine as a marker on coagulation activity in patients with suspected pulmonary embolism

Introduction

We have recently reported that increased levels of urine prothrombin fragment 1 + 2 reflected radiologically verified deep vein thrombosis. In this study we evaluated whether urine prothrombin fragment 1 + 2 was associated with pulmonary embolism in non-selected patients.

Materials and methods

Patients with clinical suspected pulmonary embolism were interviewed on comorbidities and medications. Urine was collected from each patient before radiological examination and snap frozen until analysed on urine prothrombin fragment 1 + 2 with an ELISA kit. Imaging of the pulmonary arteries were conducted with contrast enhanced computer tomography.

Results

Pulmonary embolism was diagnosed in 44/197 patients. Non-significantly higher urine prothrombin fragment 1 + 2 levels were found in non-selected patients with pulmonary embolism vs. those without (p = 0.324). Significantly higher urine prothrombin fragment 1 + 2 levels were found in the pulmonary embolism positive patients without comorbidities (n = 13) compared to the control group (n = 28) (p = 0.009). The calculated sensitivity, specificity and negative predictive value using the lowest detectable urine prothrombin fragment 1 + 2 level was 82%, 34% and 87%, respectively.

Conclusions

There was no significant urine prothrombin fragment 1 + 2 level difference in patients with and without pulmonary embolism. In non-comorbide pulmonary embolism positive patients the urine prothrombin fragment 1 + 2 levels were significantly higher compared to the control group. The negative predictive value found in this study indicates that uF1 + 2 has the potential to identify patients with a low risk of PE.     

Postprandial changes in the phospholipid composition of circulating microparticles are not associated with coagulation activation

Introduction

Evidence is present that the phospholipid composition of circulating cell-derived microparticles (MP) affects coagulation in vivo, and that postprandial metabolic alterations may be associated with hypercoagulable state. Our objective was to investigate whether postprandial metabolic responses affect the phospholipid composition of MP, and whether such changes are associated with coagulation activation.

Materials and Methods

Twelve healthy males were studied twice and randomly received two consecutive meals or remained fasted. Blood was collected before and at 2, 4, 6 and 8 h following breakfast. Plasma concentrations of prothrombin-F_1 + 2 and thrombin-antithrombin-complexes were measured. Numbers and cellular origin of MP were determined by flowcytometry. The phospholipid composition of MP was determined by hpTLC. In vitro procoagulant activity of MP was studied by fibrin generation.

Results

During the meal visit, plasma glucose, triglyceride and insulin levels increased, compared to baseline and the fasting visit (all P < 0.05). Postprandially, the total numbers of MP increased in time compared to the fasting visit (P < 0.05). Erythrocyte-derived MP increased (6-fold) during the meal visit, but remained constant on the fasting day (P < 0.001). On the meal versus fasting day circulating MP contained increased phosphatidylcholine (P < 0.05) and decreased sphingomyelin (P < 0.05) amounts. The amount of phosphatidylserine did not change. Concentrations of plasma F_1 + 2 and thrombin-antithrombin were similar on both days, as was the ability of MP to generate fibrin in vitro.

Conclusion

Although numbers, cellular origin and phospholipid composition of MP alter during exposure to two consecutive meals in healthy subjects, this does not lead to changes in the coagulation activation in vivo.     

Bivalirudin is inferior to heparin in preservation of intraoperative autologous blood

Introduction

Bivalirudin is used as an alternative to heparin in cardiac surgery, and may be superior to heparin with regard to platelet function. Bivalirudin however, is prone to cleavage by thrombin resulting in coagulation in areas of stasis.

Material and Methods

We compared the preservation of platelet function and the quality of anticoagulation in autologous blood of 26 cardiac surgical patients collected intraoperatively and anticoagulated ex vivo with either bivalirudin or heparin, with supplementation of bivalirudin over time and prevention of stasis.

Results

We found in both preservatives a reduction in ADP-induced platelet aggregation response over a period of 105 minutes (median, IQR: 73-141) as measured by Multiplate®. Supplementation of additional bivalirudin (23 ± 1.1 μg/ml/hr) and prevention of stasis was not able to prevent thrombin generation. We found a 5-fold increase in levels of prothrombin fragment 1 + 2 in bivalirudin preserved autologous blood as compared to heparin preserved blood (F₁₊₂ levels median 8.9 nM [quartile percentiles 4.2-12.4] vs 1.3 nM [0.6-2.1], P = 0.001 Mann-Whitney, n = 10).

Conclusions

Our study suggests that preservation of platelet function in autologous blood anticoagulated with bivalirudin is not a suitable alternative to heparin.     

Coagulation activation and ultrasound characteristics in patients with carotid artery disease

Introduction

Elevated levels of markers for thrombin activation are associated with plaque echogenicity and degree of stenosis in patients with carotid artery stenosis. The Activated Protein C-Protein C Inhibitor (APC-PCI) complex reflects activation of the Protein C system and is a measure of thrombin generation. The aim of the present study was to examine APC-PCI complex in patients undergoing thrombendartherectomy for carotid artery stenosis, and to relate the findings to clinical characteristics and plaque morphology as determined by ultrasound.

Materials and Methods

Blood was obtained from 125 patients (39 female, median age 71 years) with carotid artery stenosis admitted from September 2005 to May 2007. The APC-PCI complex was measured using a sandwich immunofluorometric method and compared to an age- and sex-matched healthy control-group. Clinical and demographic characteristics, routine laboratory markers and ultrasound characteristics were analysed using univariate and multivariate analysis.

Results

APC-PCI complex concentration was significantly increased in patients with carotid artery stenosis (median 0.21 µg/L; 10th to 90th percentile 0.15-0.36) compared to a healthy control-group (0.19 µg/L; 0.11-0.31; P = .009). There was no significant difference in APC-PCI-values between asymptomatic (n = 48) and symptomatic (n = 77) patients with carotid artery stenosis (0.22 vs. 0.20 µg/L; p = 0.626). Patients with minor stroke (n = 31) had a higher median APC-PCI-concentration (0.27 µg/L; 0.15-0.63) than patients with amaurosis fugax (0.19 µg/L; 0.15-0.36) or transient ischemic attack (0.21 µg/L; 0.12-0.36) (p = 0.016). No association was found between APC-PCI-values and the degrees of carotid artery stenosis or the time from the latest neurological symptoms to blood sampling. Patients with echolucent plaques had significantly lower APC-PCI concentrations (0.20 µg/L; 0.14-0.35 vs. 0.24 µg/L; 0.15-0.60; p = 0.043), according to the Gray-Weale classification.

Conclusions

Patients with carotid artery disease exhibit increased concentrations of APC-PCI compared to a healthy control-group, particularly those patients with echogenic plaques, who have significantly higher APC-PCI levels than patients with echolucent plaques.     

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.     

Efficacy and safety of enoxaparin in Japanese patients undergoing curative abdominal or pelvic cancer surgery: Results from a multicenter, randomized, open-label study

Background

Enoxaparin sodium (enoxaparin) is used worldwide for the prevention of venous thromboembolism (VTE). Registration trials of enoxaparin have been conducted primarily in Caucasian populations, and its preventive use in Japanese patients has yet to be established. To address this, we evaluated the efficacy and safety of postoperative enoxaparin in Japanese patients undergoing surgery for abdominal cancer.

Methods

This multicenter, open-label study randomized 151 Japanese patients undergoing curative surgery for abdominal cancer to enoxaparin 20 mg twice daily for 14 days, started 24-36 hours after surgery (n = 113) or intermittent pneumatic compression (IPC) as a reference (n = 38). IPC was performed at least once in both groups between randomization and surgery. The primary efficacy endpoint was the incidence of VTE in the modified intention-to-treat (mITT) population. The primary safety outcome was the incidence of any bleeding during treatment and follow-up.

Results

Incidence of VTE was 1.2% (95% CI, 0.03-6.53%) (1/83 patients) in the enoxaparin group and 19.4% (95% CI, 7.45-37.47%) (6/31 patients) in the IPC group. In the safety population, 10/109 patients in the enoxaparin group (9.2%; 95% CI, 4.49-16.23%) and 3/38 patients in the IPC group (7.9%; 95% CI, 1.66-21.38%) experienced a bleeding event. There were no cases of fatal bleeding or bleeding into any critical organ.

Conclusions

These favorable efficacy and safety data support the use of enoxaparin (20 mg twice daily for 14 days started 24-36 hours after surgery) in Japanese patients undergoing abdominal or pelvic cancer surgery.     

Inhibition of factor XI reduces thrombus formation in rabbit jugular vein under endothelial denudation and/or blood stasis

Introduction

In addition to acquired and inherited risk factors, the growth of venous thrombus under static conditions and endothelial injury play important roles in the development of deep venous thrombosis (DVT), for which risk factors include increased plasma levels of coagulation factor XI (FXI). The aim of this study is to understand the role of FXI in venous thrombus formation under conditions of endothelial denudation and/or blood stasis.

Materials and methods

The contribution of FXI to venous thrombus formation was investigated in a rabbit model and a flow chamber system. Thrombi were induced in the rabbit jugular veins by (1) endothelial denudation, (2) vessel ligation (blood stasis) or (3) by combined endothelial denudation and vessel ligation. Blood samples were perfused on immobilized type III collagen at a wall shear rate of 70/s and then the surface area covered by platelets and fibrin was morphometrically evaluated. Prothrombin fragment 1 + 2 (F1 + 2) generation was also measured before and after perfusion.

Results

All thrombi induced in rabbit jugular veins were composed of platelets, fibrin and erythrocytes. Anti-FXI antibody significantly reduced ex vivo plasma thrombin generation initiated by ellagic acid but not by tissue factor, and in vivo thrombus formation under endothelial denudation and/or vessel ligation. The antibody significantly reduced surface areas covered by platelets and fibrin, as well as F1 + 2 generation at a wall shear rate of 70/s in flow chambers.

Conclusion

These results suggest that FXI contributes to venous thrombus growth under conditions of endothelial denudation and/or blood stasis, and that thrombin generation by FXI interaction promotes further platelet aggregation and fibrin formation at low shear rates.     

A clinical-laboratory approach contributing to a rapid and reliable diagnosis of heparin-induced thrombocytopenia

Introduction

Heparin-induced thrombocytopenia (HIT) remains a very challenging diagnosis. The first objective of this study was to compare the performance of the ID-H/PF4 PaGIA^® with the Asserachrom^® HPIA ELISA. The main purpose was to evaluate the diagnostic utility of the combination of the H/PF4 PaGIA^® with the clinical “4T's” score as a screening strategy.

Materials and Methods

102 patients with clinical suspicion of HIT were classified into risk groups using the 4T's score. The presence of HIT antibodies was assessed by two immunoassays and confirmed by a functional flow cytometric assay.

Results

Comparison of the ID-H/PF4 PaGIA^® with the Asserachrom^® HPIA ELISA demonstrated a comparable technical performance, being an excellent screening test to rule out HIT (negative predictive value or NPV = 100%). According to the 4T's score, HIT was excluded in all low risk patients (NPV = 100%). ELISA optical density levels were significantly different between all risk groups (P-values < 0.01). In contrast, due to the low positive predictive value (22%) and weak positive likelihood ratio (2.6), a positive ID-H/PF4 PaGIA^® result did not considerably increase the probability of HIT.

Conclusion

Our study confirms the combination of the 4T's score with the ID-H/PF4 PaGIA^® as a reliable strategy to rule out HIT. Yet, confirming positive ID-H/PF4 PaGIA^® results by flow cytometry within 1-2 h after blood sampling remains necessary. This novel clinical-laboratory approach can contribute in a rapid and reliable way to the definite diagnosis of HIT.