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Thrombosis research [journal]
- Anti-thrombosis effect of LRRFIP1 shRNA lentivirus in a mouse model of deep vein thrombosis. [JOURNAL ARTICLE]
- Thromb Res 2013 Jun 7.
INTRODUCTION:Deep vein thrombosis (DVT) is one of the common complications of orthopedic surgery. Low molecular weight heparin (LMWH) is a usually used agent for DVT, but it would increase the risk of bleeding. LRRFIP1 has been shown to play an important role in the formation of thrombosis. Therefore, we investigated the effect of LRRFIP1 shRNA lentivirus on DVT in mice.
MATERIALS AND METHODS:Lentiviral Vectors carrying LRRFIP1 shRNA were constructed and transfected into cultured mouse bone marrow cells (BMCs). Male ICR mice were irradiated with a single dose of 9.5Gy and then were injected with different agents through the tail vein. Stasis venous thrombosis was induced by inferior vena cava (IVC) ligation. Mice were sacrificed on the 1st, 3rd and 7th day post operation and the thrombi were removed, blotted the excess blood on it with filter paper and immediately weighed. P-selectin and d-Dimer were determined by enzyme-linked immunosorbent assay (ELISA).
RESULTS:LRRFIP1 shRNA significantly suppressed the expression of LRRFIP1 in the thrombi. In contrast, low molecular weight heparin (LMWH) and negative shRNA exhibited little effect on the expression of LRRFIP1. LRRFIP1 shRNA, LMWH and negative shRNA inhibited the thrombus formation in vivo significantly. The plasma P-selectin and d-Dimer levels were significantly increased after IVC ligation. LRRFIP1 shRNA significantly decreased the plasma P-selectin and d-Dimer levels. However, LMWH and negative shRNA showed little effects on the levels of plasma P-selectin and d-Dimer.
CONCLUSION:LRRFIP1 shRNA might represent a promising prevention strategy for DVT.
- Activation of the contact system in patients with a first acute myocardial infarction. [JOURNAL ARTICLE]
- Thromb Res 2013 Jun 7.
INTRODUCTION:The contribution of the contact system to arterial thrombosis is unclear, results of clinical studies are conflicting. Particularly, little is known about the involvement of the contact system in the progression of arterial thrombosis. Therefore, we investigated the activation of the contact system during an acute myocardial infarction (AMI) and 3 and 6months following the acute event.
METHODS:Plasma of patients with a first AMI was collected on admission and 3 and 6months after the AMI. The levels of complexes of activated factor XI (FXIa), FXIIa and kallikrein with C1 esterase inhibitor (C1INH) and the levels of complexes of FXIa with α1-antitrypsin (AT) were measured in these plasmas. Recurrent cardiovascular events were recorded during a one year period after the AMI.
RESULTS:We observed that the levels of FXIa-C1INH were elevated during the acute phase compared to the steady-phase 3 and 6months after the AMI. The levels of FXIa-AT, FXIIa-C1INH and kallikrein-C1INH did not change over time. The levels of FXIa-C1INH, FXIa-AT, FXIIa-C1INH and kallikrein-C1INH were not predictive for a recurrent event.
CONCLUSION:We observed that during an AMI, the activation of FXI was increased. The levels of FXIIa-C1INH were not elevated, suggesting that activation of FXI during the acute phase did not result from contact activation. The levels of the enzyme inhibitor complexes were not predictive for a recurrent event one year after the first AMI.
- Management of cardiovascular disease in haemophilia. [JOURNAL ARTICLE]
- Thromb Res 2013 Jun 6.
Improvements in the management of haemophilia have led to a significant increase in the life expectancy of haemophilia patients, which is now close to the life expectancy in the general male population. Therefore, age-related conditions, especially cardiovascular disease (CVD), have become increasingly common in these patients. The management of CVD, especially that of coronary artery disease (CAD), acute coronary syndrome (ACS) and atrial fibrillation (AF), is particularly challenging in patients with haemophilia due to the need to find an adequate balance between bleeding and ischemic risk, requiring close coordination between cardiologists and haemophilia specialists. However, specific recommendations and relevant literature and data are scarce. Therefore, we propose pragmatic and practical therapeutic suggestions, based on the available literature and our own experience, for the management of ACS, stable angina and AF in patients with haemophilia. Overall, evidence and experience suggest that they should be treated much in the same way as the general CVD population, following standard guidelines, while choosing available treatment options known to be associated with low rates of bleeding complications. Treatments advocated for patient with haemophilia include antiplatelet therapy (aspirin and P2Y12 inhibitors), antithrombin therapy such as heparin or bivalirudin, glycoprotein IIb/IIIa inhibitors (GPIIb/IIIa inhibitors), transradial cardiac catheterization, and use of bare metal (BMS) or drug-eluting stents (DES). Antithrombotic agents with shorter half-lives that are reversible or have an antidote offer a safer choice in this setting. In addition, optimal clotting factor replacement therapy should be tailored to the increased risk of bleeding associated with invasive procedures and antithrombotic therapies, particularly during the acute phase of ACS.
- Lipoprotein-associated phospholipase A2 and venous thromboembolism: A prospective study. [JOURNAL ARTICLE]
- Thromb Res 2013 Jun 6.
INTRODUCTION:Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory marker associated positively with atherothrombotic risk. Whether Lp-PLA2 is related to risk of venous thromboembolism (VTE) is incompletely studied.
METHODS:We assessed Lp-PLA2 activity in 10,687 Atherosclerosis Risk in Communities (ARIC) Study participants and followed them a median of 8.3years (from 1996-98 through 2005) for VTE occurrence (n=226).
RESULTS:There was no significant association between baseline Lp-PLA2 quartiles and risk of VTE, neither overall nor stratified as provoked or unprovoked. Adjusted for other risk factors, the hazard ratios (95% confidence interval) of total VTE across quartiles of Lp-PLA2 were 1.0 (reference), 0.95 (0.64, 1.42), 1.03 (0.69, 1.56), and 1.26 (0.83, 1.91). In the subset of participants with LDL-cholesterol ≥130mg/dL, hazard ratios of total VTE were 1.00, 1.39 (0.44, 4.44), 2.45 (0.84, 7.11), and 2.84 (0.99, 8.14).
CONCLUSION:Our study does not support the overall hypothesis that elevated Lp-PLA2 contributes to VTE occurrence in the general population. However, in the presence of high LDL-cholesterol there was some evidence that Lp-PLA2 may increase VTE risk.
- The economic costs of routine INR monitoring in infants and children - Examining point-of-care devices used within the home setting compared to traditional anticoagulation clinic monitoring. [JOURNAL ARTICLE]
- Thromb Res 2013 Jun 5.
INTRODUCTION:The use of point-of-care (POC) devices within the home for routine INR monitoring has demonstrated reliability, safety and effectiveness in the management of infants and children requiring long-term warfarin therapy. However, a comprehensive cost-analysis of using this method of management, compared to attending anticoagulation clinics has not been reported. The aim of this study was to compare the estimated societal costs of attending anticoagulation clinics for routine INR monitoring to using a POC test in the home.
MATERIALS AND METHODS:This study used a comparative before-and-after design that included 60 infants and children managed via the Haematology department at a tertiary paediatric centre. Each participant was exposed to both modes of management at various times for a period of ≥3months. A questionnaire, consisting of 25 questions was sent to families to complete and return. Data collected included: the frequency of monitoring, mode of travel to and from clinics, total time consumed, and primary carer's income level.
RESULTS:The home monitoring cohort saved a total of 1hour 19minutes per INR test compared to attending anticoagulation clinics and had a cost saving to society of $66.83 (AUD) per INR test compared to traditional care; incorporating health sector costs, travel expenses and lost time.
CONCLUSIONS:The traditional model of care requires a considerable investment of time per test from both child and carer. Home INR monitoring in infants and children provides greater societal economic benefits compared to traditional models.
- Postpartum wound and bleeding complications in women who received peripartum anticoagulation. [JOURNAL ARTICLE]
- Thromb Res 2013 Jun 1.
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. 778ml, 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.
- ADP-induced platelet aggregation and thrombin generation are increased in Essential Thrombocythemia and Polycythemia Vera. [JOURNAL ARTICLE]
- Thromb Res 2013 Jun 1.
INTRODUCTION:Essential Thrombocythemia (ET) and Polycythemia Vera (PV) patients are characterized by an increased rate of thrombotic complications and by several abnormalities of platelets, more pronounced in JAK2V617F positive patients. The aim of this study was to characterize the platelet aggregation as well as the platelet procoagulant potential induced by several different agonists in ET and PV patients.
MATERIALS AND METHODS:Venous blood samples were obtained from 65 ET and 51 PV patients. Whole blood impedance aggregometry was utilized to characterize platelet aggregation induced by collagen, ADP, thrombin receptor activating peptide and arachidonic acid, while the Calibrated Automated Thrombogram (CAT) assay was used to determine the thrombin generation (TG) potential induced by ADP in platelet-rich plasma. CAT assay was also performed in the presence of annexin V to evaluate the contribution of platelet phospholipids to TG.
RESULTS AND CONCLUSIONS:ADP-induced platelet aggregation and TG were significantly increased in ET and PV patients compared to controls. The highest values were observed in JAK2V617F positive patients and in patients on aspirin. In these subjects, annexin V was less effective in inhibiting both basal and ADP-induced TG. This study demonstrates for first time that platelets from ET and PV patients are more responsive to the ADP stimulus, in terms of both increased platelet aggregation, and enhanced TG, particularly in the JAK2V617F positive patients. Our data support the hypothesis that the use of ADP receptor inhibitors, in addition to aspirin, might be considered in the prevention of thrombosis in these conditions, by allowing a more complete inhibition of platelet functions.
- Pharmacodynamics of recombinant activated factor VII and plasma-derived factor VII in a cohort of severe FVII deficient patients. [JOURNAL ARTICLE]
- Thromb Res 2013 May 31.
Recombinant activated factor VII (rFVIIa) and plasma-derived factor VII (pdFVII) are used to prevent bleedings in severe FVII deficient patients, despite their short half-lifes. It is suggested that FVII levels of 15-20IU/dL are sufficient to maintain hemostasis. We analyzed the pharmacodynamic effects of FVII substitution therapy in the Nijmegen Hemostasis Assay (NHA) that simultaneously measures thrombin and plasmin generation. Ten severe FVII deficient patients were treated with 20μg/kg rFVIIa or 25IU/kg pdFVII in a cross-over design. Thrombin generation lag-time (TG-LT) was identified as an effect-response parameter. Pharmacodynamic analysis using a maximum effect model showed 50% reduction of the TG-LT effect at ~2IU/dL FVII activity for both rFVIIa and pdFVII. The FVII activity to obtain TG-LT comparable to the upper limit of normal range in healthy controls (4min) was given by the effective concentration (ECnormal), showing sufficient hemostasis at 3-4IU/dL FVII activity. No association was seen between FVII activity and other thrombin or plasmin generation parameters as measured by NHA. In conclusion, 3-4IU/dL FVII activity seems sufficient to maintain hemostasis in patients with severe FVII deficiency during prophylaxis. These data may suggest a potential value for measurement of TG-LT in the monitoring of FVII(a) therapy.
- Platelet Tissue Factor: To Be Or Not To Be. [EDITORIAL]
- Thromb Res 2013 May 31.
- Difference in the D-dimer rise between women with singleton and multifetal pregnancies. [Journal Article]
- Thromb Res 2013 Jun; 131(6):493-6.
The differences in the d-dimer rise between women with singleton and multifetal pregnancies have not been studied extensively.d-Dimer levels were determined in 1089 blood specimens from 1089 women in various stages of pregnancy, including 977 and 112 women with singleton and multifetal pregnancies, respectively. None of the 1089 women developed hypertension or clinical venous thromboembolism during pregnancy or in the postpartum period.The d-dimer levels were significantly and positively correlated with gestational week at examination in women with singleton or multifetal pregnancies. The d-dimer levels (μg/ml, mean±SD [number of specimens]) determined at the 1st trimester did not differ significantly (0.81±0.82  for singleton vs. 1.20±0.77  for multifetal), but those at the 2nd (1.61±1.45  vs. 2.62±2.26 ) and 3rd (2.37±2.22  vs. 4.02±2.14 ) trimesters were significantly higher in women with multifetal than singleton pregnancies. The 90th percentile value was 4.31μg/ml for 1089 specimens. A significantly greater number of women exceeded 4.31μg/ml during the 2nd (16.9% vs. 5.6%, P=0.0043) and 3rd (34.8% vs. 10.6%, P<0.0001) trimesters among those with multifetal than with singleton pregnancies.The degree of d-dimer rise in pregnancy was greater in women with multifetal than with singleton pregnancies.