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1.
Introduction
Aspirin is often used to prevent thrombosis in pediatric cardiac surgery. The primary study aim was to assess aspirin resistance in this context. Secondary aims were to evaluate (1) the relationship between elevated inflammatory markers and thrombosis and (2) aspirin's effect on these levels.Materials and Methods
This was a prospective observational study of children undergoing cardiac surgery managed with and without aspirin. Aspirin response was assessed using the VerifyNow™ system and urinary 11-dehydrothromboxane B2 (uTxB2) measurements. Laboratory studies of inflammation were also obtained.Results
101 subjects were studied; 50 received aspirin. Six subjects (5.9%), 5 aspirin-treated, experienced symptomatic thrombosis. When measured by VerifyNow™ resistance was 43% after aspirin suppositories and 14% after additional days of oral aspirin. There was no correlation with thrombosis. Upper quartile post-operative day (POD) #5 uTxB2 was correlated with thrombosis in aspirin treated subjects (p < 0.01). High risk aspirin-treated subjects who experienced thrombosis had higher POD#5 uTxB2. This finding did not reach statistical significance (p = 0.07). Elevated pre-operative C-reactive protein (CRP) was independently associated with thrombosis (p < 0.02) in all subjects and in high risk subjects (p = 0.01). Inflammatory markers were not affected by aspirin.Conclusions
Aspirin inhibited ex-vivo platelet function with a low incidence of resistance. Elevated POD#5 uTxB2 and pre-operative CRP were correlated with thrombosis in aspirin treated subjects. Further studies are needed to determine whether children with high levels of uTxB2 despite aspirin therapy and/or those with elevated preoperative CRP are at increased risk for thrombosis. 相似文献2.
Introduction
Diabetes mellitus is complicated by accelerated atherosclerosis, resulting in an increased risk of coronary artery disease (CAD) and thrombosis. Despite the proven benefits of aspirin, previous studies indicate a reduced cardiovascular protection from aspirin in diabetic patients. We aimed to investigate whether diabetes mellitus influenced the platelet response to aspirin in patients with CAD.Materials and Methods
Platelet aggregation and activation were evaluated during aspirin treatment in 85 diabetic and 92 non-diabetic patients with CAD. Adherence to aspirin was carefully controlled. All patients had CAD verified by coronary angiography and were taking 75 mg non-enteric coated aspirin daily.Results
Diabetic patients showed significantly higher levels of platelet aggregation compared to non-diabetic patients evaluated by VerifyNow® Aspirin (p = 0.03) and Multiplate® aggregometry using arachidonic acid (AA) 0.5 mM (p = 0.005) and 1.0 mM (p = 0.009). In addition, platelet activation determined by soluble P-selectin was significantly higher in diabetics compared to non-diabetics (p = 0.005). The higher AA-induced aggregation was associated with higher levels of HbA1c. Compliance was confirmed by low levels of serum thromboxane B2 (below 7.2 ng/mL). Diabetics had significantly higher levels of serum thromboxane B2 (p < 0.0001).Conclusions
Diabetic patients with CAD had significantly higher levels of both platelet aggregation and activation compared to non-diabetic patients with CAD despite treatment with the same dosage of aspirin. These findings may partly explain the reduced cardiovascular protection from aspirin in diabetic patients. 相似文献3.
Introduction
Platelet hyperreactivity associates with cardiovascular events in humans. Studies in mice and humans suggest that prostaglandin E2 (PGE2) regulates platelet activation. In mice, activation of the PGE2 receptor subtype 3 (EP3) promotes thrombosis, but the significance of EP3 in humans is less well understood.Objectives
To characterize the regulation of thromboxane-dependent human platelet activation by PGE2.Patients/Methods
Platelets collected from nineteen healthy adults were studied using an agonist of the thromboxane receptor (U46,619), PGE2, and selective agonists and/or antagonists of the EP receptor subtypes. Platelet activation was assayed by (1) optical aggregometry, (2) measurement of dense granule release, and (3) single-platelet counting.Results
Healthy volunteers demonstrated significant interindividual variation in platelet response to PGE2. PGE2 completely inhibited U46,619-induced platelet aggregation and ATP release in 26% of subjects; the remaining 74% had partial or no response to PGE2. Antagonism of EP4 abolished the inhibitory effect of PGE2. In all volunteers, a selective EP2 agonist inhibited U46,619-induced aggregation. Furthermore, the selective EP3 antagonist DG-041 converted all PGE2 nonresponders to full responders.Conclusions
There is significant interindividual variation of platelet response to PGE2 in humans. The balance between EP2, EP3, and EP4 activation determines its net effect. PGE2 can prevent thromboxane-induced platelet aggregation in an EP4-dependent manner. EP3 antagonism converts platelets of nonresponders to a PGE2-responsive phenotype. These data suggest that therapeutic targeting of EP pathways may have cardiovascular benefit by decreasing platelet reactivity. 相似文献4.
Wolzt M Eriksson UG Gouya G Leuchten N Kapiotis S Elg M Schützer KM Zetterstrand S Holmberg M Wåhlander K 《Thrombosis research》2012,129(4):e83-e91
Introduction
AZD0837 and ximelagatran are oral direct thrombin inhibitors that are rapidly absorbed and bioconverted to their active forms, AR-H067637 and melagatran, respectively. This study investigated the antithrombotic effect of AZD0837, compared to ximelagatran and the vitamin K antagonist (VKA) phenprocoumon (Marcoumar®), in a disease model of thrombosis in patients with non-valvular atrial fibrillation (NVAF).Methods
Open, parallel-group studies were performed in NVAF patients treated with VKA, which was stopped aiming for an international normalized ratio (INR) of ≤ 2 before randomization. Study I: 38 patients randomized to AZD0837 (150, 250 or 350 mg) or ximelagatran 36 mg twice daily for 10-14 days. Study II: 27 patients randomized to AZD0837 250 mg twice daily or VKA titrated to an INR of 2-3 for 10-14 days. A control group of 20 healthy elderly subjects without NVAF or anticoagulant treatment was also studied. Size of thrombus formed on pig aorta strips was measured after a 5-minute perfusion at low shear rate with blood from the patient/control subject.Results
Thrombus formation was inhibited by AZD0837 and ximelagatran. Relative to untreated patients, a 50% reduction of thrombus size was estimated at plasma concentrations of 0.6 and 0.2 μmol/L for AR-H067637 and melagatran, respectively. For patients receiving VKA treatment, the thrombus size was about 15% lower compared with healthy elderly controls.Conclusions
Effects of AZD0837 and ximelagatran on thrombus formation were similar or greater than for VKA therapy and correlated with plasma concentrations of their active forms. 相似文献5.
Introduction
Several dietary intervention studies examining the health effect of soy isoflavones allude to the importance of equol in establishing the cardiovascular response to soy protein. Although, the specific mechanism by which this action occurs has not been established. The aim of this study was to investigate the inhibitory effect of soy-isoflavones and the metabolite of daidzein, equol, on agonist-induced platelet responses dependent on thromboxane A2 (TxA2) receptor.Material and methods
Competitive radioligand binding assay was used to screen for affinity of these compounds to the TxA2 receptor. The effect of equol on platelet activation, evaluate through of release of the ATP, by analogs of TxA2 was analyzed. The effect of equol on platelet aggregation was investigated with ADP, U46619 (a TxA2 mimic) and the calcium ionophore A23187.Results
The data showed that aglycone isoflavones and equol bind to TxA2 receptor in the µmol/L range, whereas their glucoside derivates had very low binding activity for this receptor. Under equilibrium conditions, the following order of the relative affinity in inhibiting [3H]-SQ29585 binding was: equol > genistein > daidzein > glycitein ? genistin, daidzin, glycitin. Equol interaction was reversible and competitive for labeled-SQ29548 with not apparent decrease in the number of TxA2 binding sites. In addition, from platelet activation studies, equol effectively inhibited ATP secretion elicited by the TxA2 analog U46619. On the other hand, equol inhibited the platelet aggregation induced by U46619 and A23187, while it failed to inhibit that induced by ADP.Conclusions
The aglycone isoflavones from soy, and particularly equol, have been found to have biological effects attributable to thromboxane A2 receptor antagonism. These findings may help elucidate how dietary isoflavone modulate platelet function and explain why soy-rich foods are claimed to have beneficial effects in the prevention of thrombotic events. 相似文献6.
Morishima Y Honda Y Kamisato C Tsuji N Kita A Edo N Shibano T 《Thrombosis research》2012,130(3):514-519
Introduction
Factor Xa (FXa) is a key serine protease in the coagulation cascade and a promising target for a new antithrombotic agent. Edoxaban is an oral, selective and direct FXa inhibitor. The objective of this study was to compare the antithrombotic and haemorrhagic effects of edoxaban with clinically available anticoagulants, warfarin and enoxaparin, in rat models of thrombosis and haemorrhage.Methods
Rats were treated with single oral administration of edoxaban, repeated oral dosing of warfarin for 4 days and single subcutaneous administration of enoxaparin before thrombosis or haemorrhage induction. Thrombosis was induced by the insertion of a platinum wire into the inferior vena cava for 60 min. Tail template bleeding time was measured after making an incision on the tail.Results
Edoxaban at 0.3, 1 and 3 mg/kg exerted dose-dependent and significant inhibition of venous thrombus formation. The 50% thrombus inhibition dose (ED50) was 1.9 mg/kg. At supra-therapeutic doses (10 and 20 mg/kg), edoxaban significantly but moderately (less than 2-fold) prolonged bleeding time. Warfarin and enoxaparin also dose-dependently inhibited venous thrombosis and prolonged bleeding time. The ED50 values of warfarin and enoxaparin were 0.12 mg/kg and 500 IU/kg, and the 2-fold bleeding time prolongation doses (BT2) were 0.16 mg/kg and 1700 IU/kg, respectively. The safety margin (ratio of BT2 to ED50) of edoxaban (> 10.5) was greater than those of warfarin (1.3) and enoxaparin (3.4).Conclusions
Edoxaban inhibited venous thrombosis comparably to warfarin and enoxaparin, and the attendant bleeding risk of edoxaban was lower than that of warfarin and enoxaparin in rats. 相似文献7.
Simpson ML Goldenberg NA Jacobson LJ Bombardier CG Hathaway WE Manco-Johnson MJ 《Thrombosis research》2011,127(4):317-323
Introduction
Thrombin and plasmin are the key enzymes involved in coagulation and fibrinolysis, respectively. Plasma coagulative and fibrinolytic potentials in normal children and adults, and in representative pathologically altered hemostatic states, were evaluated via simultaneous assessment of thrombin and plasmin generation.Materials and Methods
An assay of Simultaneous Thrombin and Plasmin generation (STP) was developed to measure thrombin and plasmin in plasma using individual fluorometric substrates. Coagulation is initiated with dilute tissue factor, phospholipid, and calcium in platelet-poor plasma; fibrinolysis is accelerated via tissue plasminogen activator (tPA). Abnormal states of hemostasis were investigated.Results
STP assay reproducibility and normal adult and pediatric values for measured and calculated parameters have been established. Onset of both thrombin and plasmin generation was significantly delayed in children relative to adults (p < 0.001) and the maximum amplitudes of thrombin and plasmin generation were less in children than adults (p < 0.01). No significant differences were measured among pediatric age groups. The most profound impairments in thrombin generation were observed for extrinsic and common pathway factor deficiencies, with the exception of afibrinogenemia. Plasmin generation was severely impaired in deficiencies of fibrinogen and plasminogen as well as with decreased tPA reagent concentration and addition of aminocaproic acid. Plasmin generation was greatly enhanced by alpha-2-antiplasmin deficiency and excess tPA reagent.Conclusion
Simultaneous assessment of thrombin and plasmin generation in plasma shows promise for affording an enhanced understanding of overall coagulative and fibrinolytic functions in physiological and pathologically altered states of hemostasis in children and adults. 相似文献8.
V. Pengo G. Denas A. Banzato P. Gresele N. Erba A. Ghirarduzzi B. Montaruli S. Testa A. Tripodi 《Thrombosis research》2010,126(2):150-153
Objective
Anti-prothrombin (aPT) antibodies have been found in Lupus Anticoagulant (LA) positive patients. Their prevalence and relative contribution to thromboembolic risk in LA-positive patients is not well defined. The aim of this study was to determine their presence and association with thromboembolic events in a large series of patients with confirmed LA.Methods
Plasma from LA-positive patients was collected at Thrombosis Centers and sent to a reference central laboratory for confirmation. Positive plasma was tested using home-made ELISA for the presence of aPT and anti-β2GPI antibodies.Results
LA was confirmed in 231 patients. Sixty-one of 231 (26%, 95%CI 22-33) LA positive subjects were positive for IgG aPT and 62 (27%, 95% CI 21-33) were positive for IgM aPT antibodies. Clinical features of Antiphospholipid Syndrome (APS) were not associated with the presence of IgG aPT [43 APS in 61 (70%) positive and 109 APS in 170 (64%) negative IgG aPT subjects, p = ns] or IgM aPT. Rate of positivity of IgG and IgM aβ2GPI was significantly higher than that of IgG and IgM aPT. Clinical events accounting for APS occurred in 97 of 130 (75%) IgG aβ2GPI positive and in 55 of 101 (54%) IgG aβ2GPI negative patients (OR 2.4, 95% CI 1.4 to 4.3, p = 0.002). No significant association with clinical events in patients positive for both IgG aPT and IgG aβ2GPI as compared to those positive for one or another test was found. When patients negative for both IgG aPT and IgG aβ2GPI (LA positive only) were compared with remaining patients, a significantly lower association with clinical events was found (OR = 0.4, 95% CI: 0.2 to 0.7, p = 0.004).Conclusions
As compared to IgG aβ2GPI, the prevalence of IgG aPT in patients with LA is significantly lower and not associated with the clinical features of APS. 相似文献9.
Introduction
As ticagrelor, clopidogrel and cangrelor therapies may be used in the same clinical setting, their potential pharmacodynamic interactions are of interest. Hence, we investigated possible interactions between these agents in dogs using a variety of switching protocols.Methods
Six male dogs all received 7 different dosing regimens separated by 1-5 week washout periods: cangrelor (1 μg/kg/min, intravenous infusion); ticagrelor (0.8 mg/kg, oral); clopidogrel (3 mg/kg, intravenous injection); cangrelor together with ticagrelor initiated 10 minutes after cangrelor infusion start or clopidogrel given 30 minutes after cangrelor infusion start; ticagrelor followed by clopidogrel given 3 or 7 hours after ticagrelor dosing. ADP-induced whole blood platelet aggregation was measured by impedance aggregometry.Results
Mean maximum inhibition of platelet aggregation (IPA) was 81-87% at 6 minutes (cangrelor), 3 hours (ticagrelor) and 4 hours (clopidogrel) postdosing and platelet function recovered after 1.5 hours, 12 hours, and 9 days, respectively. IPA at 2 hours post clopidogrel was reduced to 39% when clopidogrel was given during cangrelor infusion versus 69% for clopidogrel alone. With clopidogrel dosed 3 hours after ticagrelor, IPA was reduced after washout of ticagrelor to 38% at 24 hrs vs. 68% for clopidogrel alone, but an interaction was not seen when clopidogrel was dosed 7 hours after ticagrelor. No pharmacodynamic interaction occurred between ticagrelor and cangrelor.Conclusions
The extent of the pharmacodynamic drug-drug interactions observed between clopidogrel and cangrelor or ticagrelor apparently depends on the level of receptor occupancy when clopidogrel is administered. Importantly, no significant pharmacodynamic interaction occurred between ticagrelor/clopidogrel when clopidogrel was given at clinical trough IPA levels with ticagrelor. No significant pharmacodynamic interaction occurred with cangrelor and ticagrelor. 相似文献10.
Background
Venous thrombosis is a complication of treatment of children with cancer but studies devoted to the epidemiology of thrombosis in children with cancer are rare and data are scanty.Objective
To determine the prevalence and clinical characteristics of VT as a secondary complication in children with malignant disease and to estimate the ten-year experience of our hospital.Method
Retrospective analysis of data of Children's Cancer Subregistry of Belarus, which included information about age, gender, details of diagnosis, classification of malignant neoplasm according to ICD-10, treatment protocol and outcome. Clinical information was obtained from case histories.Results
For the specified period, 2061 children with newly diagnosed cancer and 44 cases of VT have been registered. Among VT cases, hematological malignancies prevailed (32 of total 44). Higher incidence of VT in AML and APL groups was shown (p‹0.05). In patients with VT, boys (M/F = 1,6/1) and teenagers prevailed (65,9%). Of 44 patients, 33 had catheter-associated thrombosis (CAT). Almost all CAT (91,7%) were in the upper venous system. Children with non-CAT (11 out of 44) had more prolonged duration of immobilization, than children with CAT (p‹0.05) and in this group, thrombosis affected predominantly the lower limb (9 out of 11).Conclusion
The present study has shown that venous thrombosis occurs significantly more often in children with AML and APL. Prevalence of boys in patients with venous thrombosis has been noted. Increased frequency of VT events in teenagers has been observed and the provoking role of CVC and immobilization for thrombosis has been confirmed. 相似文献11.
Introduction
In South Africa coronary artery disease (CAD) is less common in African than Indian or white subjects. Although the association between CAD and metabolic factors have been well documented, the role of genetic factors is as yet poorly understood. Specific polymorphisms in the platelet membrane glycoprotein (GP) IIIa gene PlA1/A2, have been implicated in the development of CAD.Methods
The prevalence of platelet GPIIIa (PlA1/A2) polymorphisms and their effect on platelet function was determined in 313 Indian, 267 white and 227 African subjects with and without a history of CAD.Results
In subjects without a history of CAD the frequency of the unfavourable PlA2 allele was 8.0%, 14.8% and 8.7% in the Indian, white and African populations respectively, with the frequency being significantly higher (p < 0.05) in the white than both other groups. The frequency of the PlA2 allele was higher in subjects with (23.0%) than without (10.0%; p < 0.0001) a history of CAD. Aggregation studies showed that platelets carrying the PlA2 allele were hypersensitive to the platelet aggregating agonists ADP and collagen and produced a higher amount of TXA2 when stimulated with low concentrations of both these agonists.Conclusions
The positive association observed between the platelet GPIIIa PlA1/A2 polymorphism and platelet function suggests that the GPIIIa PlA2 allele may be a genetic factor that contributes to the risk of sudden death from myocardial infarction in the absence of known risk factors but it does not explain ethnic differences in the prevalence of CAD. 相似文献12.
Introduction
1-[4-[2-(4-Bromobenzene-sulfonamino)ethyl]phenylsulfonyl]-3-(trans-4-methylcy-clohexyl)urea(I4, CAS865483-06-3); a totally synthetic new sulfonylurea compound, combining the hypoglycemic active structure of Glimepiride (CAS 93479-97-1) and anti-TXA2 receptor (TP) active structure of BM-531(CAS 284464-46-6), was designed and synthesized. Its effects on TXA2 synthesis and TP have not been reported yet.Aim
To study the inhibitory effects of I4 and its mechanisms of action on TXA2 and TP.Methods
Platelet aggregation studies were performed on human platelet, rat whole blood platelet and rabbit platelet, platelets aggregation was induced by TP agonist U-46619(stable analog of TXA2, CAS 56985-40-1). Plasma TXB2 and 6-keto-prostaglandin F1α (6-keto-PGF1α) were used as markers to determine the effect of I4 on thromboxane synthesis. Fluo-3-AM was used to measure the cytosolic Ca2 + concentrations ([Ca2 +]i) in rabbit platelet. Aorta rings with and without endothelium were prepared and aorta contraction was induced by U-46619. A model of type 2 diabetes mellitus was established by intraperitoneal injection of low dose of streptozocin to rats fed a high-calorie diet. Both normal rats and type 2 diabetic rats were used to assay the inhibitory effect of I4 on platelet aggregation induced by U-46619.Results
I4 exhibited a higher inhibitory potency than Glimepiride on U-46619 induced platelet aggregation in vitro and in vivo. I4 increased the ratio of plasma PGI2/TXA2 and decreased [Ca2 +]i release from platelet internal stores. In addition, I4 presented a vasorelaxant activity on isolated rat aorta contraction induced by U-46619.Oral administration of I4 (1 ~ 10 mg/kg) markedly and dose-dependently inhibited platelet aggregation in both normal rats and type 2 diabetic rats.Conclusion
I4 significantly inhibited platelet aggregation induced by U-46619 in vitro and in vivo, and rat aorta contraction. It probably acts by partly blocking TXA2 action, decreasing the platelet intracellular Ca2 +, and increasing the PGI2/TXA2 ratio. 相似文献13.
Introduction
Idiopathic pulmonary arterial hypertension (IPAH) is characterized by pulmonary arteriolar narrowing and degeneration associated with in situ thrombosis. We hypothesized that microvascular endothelial injury and apoptosis may be an initiating mechanism in IPAH. Endothelial apoptosis generates endothelial microfragments (EMF), which can activate platelets. Platelets release both VEGF and angiostatin, which depending the balance can inhibit or induce endothelial apoptosis, respectively.Materials and Methods
We measured EMFs from blood of IPAH patients as index of endothelial cell apoptosis/injury and levels of pro- and anti- EC apoptotic factors found in platelets. EMFs and platelets in blood samples from control subjects and patients with IPAH were measured using a 4-color flow cytometry protocol, and platelet levels of VEGF and angiostatin were determined by ELISAs and immunoblotting.Results
Compared to controls, IPAH patients exhibited higher numbers of circulating EMFs and more activated/apoptotic platelets. IPAH patients also exhibited higher levels of platelet angiostatin; however, no significant difference was detected in platelet VEGF levels between the two groups.Conclusions
These results are consistent with an increase in EC dysfunction in patients with IPAH, possibly contributing to the progression of IPAH and its associated thrombosis. 相似文献14.
Boto LR Crispim JN de Melo IS Juvandes C Rodrigues T Azeredo P Ferreira R 《Sleep medicine》2012,13(1):88-95
Objectives
To look for an association between sleep deprivation and risk of accidental falls (AF) in children.Methods
A questionnaire was applied to two groups of children aged 1-14 years, encompassing children observed in an emergency room for AF (G1) and children attending health care visits (HV) (G2). Collected data included demographic characteristics, medical history, previous week’s sleep pattern (PWSP), sleep duration and sleep pattern in the preceding 24 h, mechanism of fall, and injury severity. Exclusion criteria: acute or chronic disease or exposure to drugs interfering with sleep. Statistical analyses included Fisher’s exact test, Pearson Chi-square, Fisher-Freeman-Halton test, T and Mann-Whitney tests for independent samples, and multivariate logistic regression (α = 5%).Results
We obtained 1756 questionnaires in G1 and 277 in G2. Of those, 834 in G1 and 267 in G2 were analyzed. We found an increased risk of AF in boys (OR 1.6; 95% CI 1.2-2.4). After controlling for age, gender, summer holidays, parental education and profession, lack of naps and PWSP were associated with increased risk (OR 2.1; 95% CI 1.3-3.3 and OR 2.7; 95% CI 1.2-6.1). In 3-5 year-old children there was an association between AF and a shorter than usual sleep duration in the previous 24 h (p = 0.02).Conclusions
To our knowledge, our study is the largest so far to assess the association between sleep deprivation and childhood injury. It evidences a protective effect of naps in children. Sleep duration of less than 8 h increases risk of AF. Pre-schoolers may be particularly susceptible to sleep deprivation. 相似文献15.
Misaki Takahashi Sayaka Moriguchi-Goto Tomoko Matsumoto Yuichiro Sato Kunihiro Hattori Yujiro Asada 《Thrombosis research》2010,125(5):464-470
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. 相似文献16.
Liu Y Yang J Xu Q Xu B Gao L Zhang Y Zhang Y Wang H Lu C Zhao Y Yin T 《Thrombosis research》2012,130(3):435-440
Introduction
Multiple warfarin pharmacogenetic algorithms have been confirmed to predict warfarin dose more accurately than clinical algorithm or the fixed-dose approach. However, their performance has never been objectively evaluated in patients under low intensity warfarin anticoagulation, which is optimal for prevention of thromboembolism in Asian patients.Material and methods
We sought to compare the performances of 8 eligible pharmacogenetic algorithms in a cohort of Chinese patients (n = 282) under low intensity warfarin anticoagulation with target international normalized ratio (INR) ranged from 1.6 to 2.5. The performance of each algorithm was evaluated by calculating the percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) between each predicted dose and actual stable dose.Results
In the entire cohort, the pharmacogenetic algorithms could predict warfarin dose with the average MAE of 0.87 ± 0.17 mg/day (0.73-1.17 mg/day), and the average percentage within 20% of 43.8% ± 8.1% (29.1% - 52.1%). By pairwise comparison, warfarin dose prediction was significantly more accurate with the algorithms derived from Asian patients (48.6% - 50.0%) than those from Caucasian patients (29.1% - 39.7%; odds ratio [OR]: 1.61-3.36, p ≤ 0.02). Algorithms with additional covariates of INR values or CYP4F2*3 performed better than those without the covariates (adding INR: OR: 1.71 (1.08-2.72), p = 0.029; adding CYP4F2*3: OR: 2.67(1.41-5.05), p = 0.004). When the patients were stratified according to the dose range, the algorithms from Caucasian and racially mixed populations tended to perform better in higher dose group (≥ 4.5 mg/day), and algorithms from Asian populations performed better in intermediate dose group (1.5-4.5 mg/day). None of the algorithms performed well in lower dose group (≤ 1.5 mg/day).Conclusions
No eligible pharmacogenetic algorithm could perform the best for all dosing range in the Chinese patients under low intensity warfarin anticoagulation. Construction of a refinement pharmacogenetic algorithm integrating 3 genotypes (CYP2C9, VKORC1 and CYP4F2) and INR data should be warranted to improve the warfarin dose prediction in such patients. 相似文献17.
Qi Zhou Lei Jiang Chunhua Xu Dongjiao Luo Chunlai Zeng Pu Liu Ming Yue Yangyang Liu Xiaosheng Hu Hu Hu 《Thrombosis research》2014
Introduction
Derived from the root of Panax ginseng C.A.Mey, Panax notoginsenosides (PNS) is a widely used herbal medicine to treat atherothrombotic diseases in Asian medicine. Ginsenoside Rg1 is one of the main compounds responsible for the pharmaceutical actions of PNS. As platelets play pivotal roles in atherothrombogenesis, we therefore studied the effect of Rg1 on platelet activation and its underlying mechanisms.Materials and Methods
Human platelets are obtained from healthy subjects. Platelet activation and the inhibition of Rg1 were assessed by Born aggregometer, flow cytmetry, flow chamber and western blot. The in vivo thrombosis model was induced by 10% FeCl3 on mesenteric arterioles of wild type B57/b6 mice.Results
Rg1 significantly inhibited platelet aggregation induced by thrombin, ADP, collagen and U46619, e.g., aggregation rate stimulated by 0.1 U mL- 1 thrombin was decreased 46% by Rg1. Rg1 also reduced thrombin (0.1 U mL- 1)-enhanced fibrinogen binding and P-selectin expression of single platelet by 81% and 66%, respectively. Rg1 affected αIIbβ3-mediated outside-in signaling as demonstrated by diminished platelet spreading on immobilized fibrinogen. Rg1 also decreased the rate of clot retraction in platelet rich plasma. Furthermore, Rg1 decreased platelet adhesion on collagen surface under a shear rate correlated to the arterial flow (1000 s- 1) by approximately 70%. Western blot showed that Rg1 potently inhibited ERK phosphrylation. The in vitro findings were further evaluated in the mouse model of in vivo arterial thrombosis, and Rg1 was found to prolong the mesenteric arterial occlusion time (34.9 ± 4.1 min without and 64.3 ± 4.9 min with Rg1; p < 0.01).Conclusions
Rg1 inhibits platelet activation via the inhibition of ERK pathway, and attenuates arterial thrombus formation in vivo. 相似文献18.
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. 相似文献19.
Hampton AL Diaz JA Hawley AE Wrobleski SK Wang JG Lee RD Kirchhofer D Sigler RE Wakefield TW Mackman N Myers DD 《Thrombosis research》2012,130(4):640-645
Introduction
Tissue factor (TF) is a potent initiator of the extrinsic coagulation cascade. The role and source of TF in venous thrombotic disease is not clearly defined. Our study objective was to identify the contribution of myeloid cell TF to venous thrombogenesis in mice.Materials and methods
The mouse electrolytic inferior vena cava model was used to induce thrombosis. The following groups of mice were used (1) TFflox/floxLysMCre+ mice that have reduced TF expression in myeloid cells, (2) TFflox/floxLysMCre- littermate controls, (3) Wild type mice given a monoclonal anti-mouse TF antibody (1H1) to inhibit TF activity, and (4) Wild type mice given rat IgG. Evaluations at baseline, day 2, and day 6 post thrombosis included thrombus weight, vein wall inflammatory cell migration, vein wall TF mRNA, and plasma D-dimer levels.Results
Inhibition of TF significantly decreased thrombus weight 2 days post venous thrombosis. In contrast, TFflox/floxLysMCre+ had no change in thrombus weight when compared to littermate controls. The absence of myeloid cell TF did not affect infiltration of neutrophils or monocytes into the vein wall. TF mRNA expression in the vein wall decreased at 2 days but then returned to baseline levels by 6 days post thrombosis. D-dimer levels peaked at 2 days post thrombosis in mice with or without myeloid cell TF.Conclusions
TF is important in the formation of venous thrombi in the macrovasculature. However, TF expression by myeloid cells does not significantly contribute to venous thrombogenesis in this model. 相似文献20.