Soluble urokinase plasminogen activator receptor in patients with abdominal aortic aneurysm

Introduction

In the present study we investigated the impact of soluble urokinase plasminogen activator receptor (suPAR) as a biomarker in patients with abdominal aortic aneurysm (AAA) in relation to conventional inflammatory markers, aneurysm size, and rupture.

Methods

suPAR and conventional inflammatory markers were measured in 119 patients with AAA and 36 controls without aneurysm matched by age, gender and smoking habit.

Results

The results support earlier studies suggesting a state of activated inflammatory response in patients with nonruptured AAA as expressed by elevated CRP and IL-6 compared with the controls. In contrast, suPAR showed similar levels in patients with nonruptured AAA compared with the controls. Unexpectedly, all follow-up patients (n = 16) have significant (p < 0.001) elevated suPAR levels three years postoperatively compared preoperatively.

Conclusions

suPAR does not seem to be a useful biomarker in the AAA disease. The role of the postoperative elevation of suPAR needs to be further elucidated.     

The relationship between aortic aneurysm sac thrombus volume on coagulation, fibrinolysis and platelet activity

Aim

Abdominal aortic aneurysm (AAA) is associated with chronic mural inflammation and a pro-thrombotic diathesis. It has been suggested that both may be related to biologically active intra-sac thrombus. The aim of this study was to examine the relationship between thrombin generation, fibrinolysis, platelet activity and AAA sac thrombus volume.

Methods

30 patients (29 men) of median (IQR) age 75 (71-82) years with an infra-renal AAA > 5.5 cm in antero-posterior diameter were prospectively studied. AAA, lumen and thrombus volumes were calculated using a CT workstation (Vitrea). Plasma thrombin-antithrombin (TAT), plasminogen activator inhibitor (PAI)-1, and soluble (s) P-selectin were measured as biomarkers of coagulation, fibrinolysis and platelet activity, respectively

Results

Median (IQR) AAA total, lumen and thrombus volumes were 188 (147-247) cm³, 80 (54.3-107) cm³ and 97.6 (63-127) cm³ respectively.TAT levels were significantly higher (median, QR, 7.15 [4.7-31.3] μg/L, p = < 0.001) and sP-selectin levels significantly lower (median, IQR, 80.5 [68-128] ng/ml, p = < 0.0001) than the normal range. PAI-1 levels (median, IQR, 20.9 [8.4-50.7] ng/ml) were normal. There was no correlation between AAA thrombus volume and PAI-1 (r = − 0.25, p = 0.47), sP-Selectin (r = 0.26, p = 0.43) or TAT plasma levels (r = − 0.21, p = 0.54).

Conclusion

The present study confirms that patients with AAA demonstrate haemostatic derangement, but the extent of the haemostatic derangement does not correlate with AAA sac thrombus volume.     

Coagulation and fibrinolysis after open infrarenal abdominal aortic aneurysm repair in a long-term perspective

In patients with abdominal aortic aneurysms (AAA) the coagulation and fibrinolytic systems have been found to be activated preoperatively. Does the increased activity of the coagulation and fibrinolytic systems persist after AAA surgery in a long-term perspective? Prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), tissue plasminogen activator (tPA), human plasminogen activator inhibitor type 1, and human cross-linked fibrin degradation product (D-dimer) were analysed in 18 patients after open AAA surgery (postop-AAA). The median time between surgery and blood sampling was 19 months (range, 5-37 months). Comparisons were made with both preoperative values of 23 patients with AAA (preop-AAA) as well as 20 age-matched healthy controls (AMC). F1+2, TAT, and D-dimer in preop-AAA were significantly higher compared to AMC (p<0.001). In post-op AAA patients these parameters were significantly lower compared to preop-AAA (p<0.05 for F1+2 and TAT, p<0.001 for D-dimer). However, TAT and D-dimer levels were still higher in postop-AAA than in AMC (p<0.01 for both). The activity of the coagulation and fibrinolytic systems seems to decrease after AAA surgery. However, the activity is still higher than in healthy AMC. A possible explanation may be that the thrombogenicity is lower in a vascular graft than in an aneurysmal sac but still higher than in a nonaneurysmal aorta.     

Expression of annexin II in human atherosclerotic abdominal aortic aneurysms

Background

Annexin II is a receptor for tissue-type plasminogen activator (t-PA) that converts plasminogen to plasmin. Although the fibrinolytic system is known to play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs), the relationship between annexin II and AAA development is unknown. Therefore, we examined annexin II localization in the wall of human atherosclerotic AAAs.

Methods and Results

Specimens from 13 patients undergoing elective repair of an AAA were taken. Annexin II expression was evaluated by immunohistochemical analysis. Immunostaining results were semiquantitatively analyzed using histology scores and WinROOF software based on staining intensity. The expression of annexin II was increased and the histology score was higher in the shoulder region of the atheromatous plaque than in the atheroma and fibrous plaque regions. Annexin II appeared to have greater expression and the histology score was higher in regions where the media was preserved. Furthermore, there was a significant inverse correlation between AAA size and histology score in the fibrous plaque region.

Conclusions

The present work demonstrates various levels of annexin II expression within the aneurysm wall. Therefore, we suggest that alteration of annexin II expression within the aortic wall may be associated with the development of an aneurysm.     

The APC-PCI concentration as an early marker of activation of blood coagulation: A study of women on combined oral contraceptives

Background

The risk of venous tromboembolism (VTE) in women taking combined oral contraceptives (COCs) is attributed to changes in coagulation and fibrinolysis. The impact of the COCs may be greater in women with preexisting thrombophilic defects. Nevertheless most women who suffer from venous thrombosis do not have any of the well known hereditary or acquired risk factors. A simple and sensitive marker of”thrombogenicity” has not been identified.

Objectives

To investigate the effects of two different monophasic combined oral contraceptives (COCs) on the plasma concentrations of activated protein C-inhibitor of protein C ( APC-PCI) and on comparable hemostatic factors in fertile women.

Method

Forty four healthy nulliparous women with regular menstrual periods were included and randomly assigned to start with a monophasic preparation containing 30 μg ethinylestradiol and 150 μg levonogestrel (LNG/EE) or a preparation containing 30 μg ethinylestradiol and 150 ug desogestrel (DG/EE). After a wash out period of two months, treatment with the alternate preparation was initiated and continued for two more cycles.

Results

The plasma concentration of the APC-PCI complex and thrombin-antithrombin complex (TAT) increased during treatment with the two COCs. During DG/EE treatment the APC-PCI complex increased significantly more than during LNG/EE (p < 0,01).The plasma concentration of D-dimer did not increase during OC treatment.

Conclusion

The APC-PCI complex concentration, which serves as a marker for thrombin generation and indicates hypercoagulability, was increased during COC treatment compared to baseline. The method is a sufficiently sensitive marker to detect even small differences in the activation of coagulation.     

Clinical probability assessment and D-dimer determination in patients with suspected deep vein thrombosis, a prospective multicenter management study

Objectives

To investigate the reliability of a combined strategy of clinical assessment score followed by a local D-dimer test to exclude deep vein thrombosis. For comparison D-dimer was analysed post hoc and batchwise at a coagulation laboratory.

Design

Prospective multicenter management study.

Setting

Seven hospitals in southern Sweden.

Subjects

357 patients with a suspected first episode of deep vein thrombosis (DVT) were prospectively recruited and pre-test probability score (Wells score) was estimated by the emergency physician. If categorized as low pre-test probability, D-dimer was analysed and if negative, DVT was considered to be ruled out. The primary outcome was recurrent venous thromboembolism (VTE) during 3 months of follow up.

Results

Prevalence of DVT was 23.5% (84/357). A low pre-test probability and a negative D-dimer result at inclusion was found in 31% (110/357) of the patients of whom one (0.9%, [95% CI 0.02-4.96]) had a VTE at follow up. Sensitivity, specificity, negative predictive value and negative likelihood ratio for our local D-dimer test in the low probability group were 85.7%, 74.5%, 98.2%, and 0,19 respectively compared to 85.6%, 67,6%, 97.9% and 0,23 using batchwise analysis at a coagulation laboratory.

Conclusion

Pre-test probability score and D-dimer safely rule out DVT in about 30% of outpatients with a suspected first episode of DVT. One out of 110 patients was diagnosed with DVT during follow up. No significant difference in diagnostic performance was seen between local D-dimer test and the post hoc batch analysis with the same reagent in the low probability group.     

Dependence of platelet function on underlying liver disease in orthotopic liver transplantation

Objective

The purpose of the present study was to explore the platelet function during the perioperative period of orthotopic liver transplantation (OLT) due to the underlying liver disease.

Methods

The blood coagulation parameters, platelet surface markers and the determination of platelet aggregation were analyzed in 34 patients who underwent OLT. Blood samples were drawn preoperatively, anhepatic, 10 min and 1 hour after reperfusion, 1 day, 3 and 7 days postoperatively. Conventional coagulation screens, thrombopoietin (TPO) serum levels, P-selectin, GPIIb/IIIa and GPIb binding sites on the surface of platelets as evaluated by flow cytometry and platelet aggregation response were measured.

Results

Coagulation factors, maximum aggregation and rate of aggregation were significantly different before transplantation due to the underlying liver disease. Further we found a markedly depressed GPIIb/IIIa and P-selectin expression and a reduced rate of aggregation in all patients throughout the study. In contrast maximum aggregation of platelets was restored on the third day after reperfusion without intergroup differences and almost comparable to healthy controls. An inverse correlation was found between peripheral platelet count pre-transplantation and peak TPO concentrations one weak post-transplantation.

Conclusions

In the entire process of OLT, coagulation factors, maximum aggregation and rate of platelet aggregation depend on the surgical phases during transplantation and on the underlying liver disease. The data obtained in this study might contribute to a better understanding of the pathophysiology and assessment of bleeding risk in OLT.     

Smoking promotes clopidogrel-mediated platelet inhibition in patients receiving dual antiplatelet therapy

Background

High on-treatment residual platelet reactivity is associated with an increased risk of adverse events after coronary stenting. Recent data suggest that cigarette smoking might enhance clopidogrel-mediated platelet inhibition. We therefore sought to investigate the influence of cigarette smoking on clopidogrel- and aspirin-mediated platelet inhibition after percutaneous intervention with stent implantation.

Patients and methods

Platelet aggregation was assessed by the VerifyNow P2Y12 and aspirin assays in 102 patients on dual antiplatelet therapy 24 hours after peripheral, coronary or carotid artery stenting. Among these, there were 33 nonsmokers, 29 former smokers and 40 current smokers. Patients in the fourth quartile of the VerifyNow assays were considered as patients with high on-treatment platelet reactivity.

Results

Current smokers had significantly lower P2Y12 Reaction Units compared with nonsmokers (p = 0.028). Former smokers also had lower adenosine diphosphate (ADP)-inducible platelet aggregation than nonsmokers, but the difference was not significant (p = 0.52). A high on-treatment residual ADP-inducible platelet aggregation was more common among nonsmokers than among current smokers (14 vs 5; p = 0.004). In a multivariate regression analysis smoking was an independent influencing variable for post-treatment ADP-inducible platelet reactivity (p = 0.026). Aspirin-mediated platelet inhibition showed no significant differences between nonsmokers and former smokers or current smokers (p > 0.3).

Conclusion

By in vitro testing, cigarette smoking is associated with enhanced clopidogrel- but not aspirin-mediated platelet inhibition. The clinical implications have to be evaluated in large prospective trials.     

Evaluation of the platelet count drop method for assessment of platelet function in comparison with “gold standard” light transmission aggregometry

Introduction

Hyporesponsiveness to antiplatelet agents has been linked to an increased risk of major adverse cardiovascular events. However, light transmission aggregometry (LTA), the gold standard methodology for assessing platelet function, requires expertise and is labour-intensive, which render its use in clinical settings impractical. We assessed whether platelet count drop (PCD), a technique widely available in any haematology laboratory, could replace LTA in testing for inhibition of platelet aggregation induced by antiplatelet agents.

Materials and methods

One hundred and sixty-one coronary artery disease patients taking aspirin alone and 91 patients taking a combination of aspirin and clopidogrel were enrolled. Platelet aggregation was measured by LTA and PCD stimulated with 1.6 mM of arachidonic acid (AA) for aspirin and 5 and 20 μM of adenosine diphosphate (ADP) for clopidogrel.

Results

Correlation between AA-induced LTA and PCD was inexistent (r = - 0.043, p = 0.587), while correlation between ADP-induced LTA and PCD was low (r = 0.374, p < 0.0001 for ADP 5 μM and r = 0.402, p < 0001 for ADP 20 μM). PCD, whether stimulated with AA or ADP, overestimated platelet aggregation as assessed by LTA, by 13-18%. The wide 95% limits of agreement suggest that the assays can disagree significantly in individual patients.

Conclusions

Although the PCD method is widely available in non-specialized laboratories, our results demonstrate that there is poor correlation with the current gold standard, i.e. LTA. Thus, PCD should not be used in replacement of LTA to assess antiplatelet responsiveness.     

Haemostatic factors in women with history of Preeclampsia

Objective

Evaluation of haemostatic parameters - Plasma tissue plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1) and fibrin fragment D-dimer several years after the end of pregnancy to investigate if they are modified in women with history of preeclampsia (PE). Study design: 65 healthy women with history of PE and 54 control women with previous normal pregnancy were enrolled in this study. Groups were matched for age, time period since delivery, smoking status and alcohol consumption. t-PA, PAI-1 and fibrin fragment D-dimer antigen levels were quantified using standards commercial ELISA methods. Plasma fibrinogen was measured using automated capillary zone electrophoresis.

Results

Systolic and diastolic blood pressures were higher in women with history of PE. Levels of t-PA, PAI-1 and fibrinogen were similar between groups as well as the t-PA/PAI-1 ratio. A significant increase in D-dimer levels was observed in women with history of PE.

Conclusion

The increase in D-dimer level suggests an abnormal haemostatic potential namely increased intravascular coagulation. This, together with the increased blood pressure, can reflect a tendency for an increased risk of cardiovascular/thrombotic events later in life.     

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.     

Prior simvastatin treatment is associated with reduced thrombin generation and platelet activation in patients with acute ST-segment elevation myocardial infarction

Background

It has been reported that statin therapy produces additional effects including impaired activation of blood coagulation. It is not clear whether statins can affect hemostasis in patients with acute coronary syndrome. The aim of this study was to investigate the effect of prior statin treatment on thrombin generation and platelet activation in patients with ST-segment elevation myocardial infarction (STEMI).

Methods

We studied 53 consecutive STEMI patients admitted within 12 hours of pain onset, including 19 treated with simvastatin (40 mg/d) (simvastatin group) at least one month prior to STEMI, and 34 not receiving any statins (no-statin group) on admission. Thrombin-antithrombin (TAT) complexes generation and soluble CD40 ligand (sCD40L) release were determined in 60-second blood samples collected at the site of microvascular injury.

Results

There were no significant intergroup differences with respect to clinical and laboratory variables, including plasma TAT and sCD40L levels, except lower total cholesterol and low-density lipoprotein cholesterol in the simvastatin group. The mean maximum rate of TAT generation was 47.5% lower (p = 0.0002) and sCD40L release 33.3% lower (p = 0.0006) in the simvastatin group. Total amounts of TAT (p < 0.0001) and sCD40L (p = 0.002) collected within 5 minutes of bleeding were lower in simvastatin-pretreated patients. By multivariate regression analysis, variables describing local TAT and sCD40L profiles in the whole group were independently associated with simvastatin pretreatment (p < 0.0001), but not with cholesterol, platelet count or troponin levels.

Conclusions

Prior simvastatin use is associated with lower thrombin generation and platelet activation following vascular injury in the early phase of STEMI.     

Prognostic value of pre-surgical plasma PAI-1 (plasminogen activator inhibitor-1) levels in breast cancer

Introduction

Plasminogen activator inhibitor (PAI-1) may have an independent prognostic value in breast cancer (BC). PAI-1 4G/5G polymorphism may have significance for antigen expression. Thus, we analyzed the possible associations between PAI-1 4G/5G polymorphism, plasma PAI-1 levels, and clinicopathological features of breast cancer (BC) patients.

Patients and Methods

PAI-1 4G/5G polymorphism (both on germinal and tumor DNA) and plasma PAI-1 levels were investigated in 99 BC patients and 50 unrelated healthy women similar for age and menopausal status.

Results

No association was found between allele frequencies and clinicopathological features of BC or plasma antigen levels. Plasma PAI-1 levels were higher in BC compared to controls (p = 0.002), particularly in patients with large tumors (p < 0.001). 5-year follow-up was achieved in 79 patients: 30% had relapsing disease, 63% with positive compared to 37% with negative PAI-1 levels (p < 0.05). 5-year relapse-free survival rate of positive PAI-1 was 46% vs., 77% of negative patients (p = 0.02).

Conclusions

We may conclude that plasma PAI-1 levels in BC patients could represent a useful prognostic variable for relapse, although PAI-1 polymorphism might not represent a genetic susceptibility factor.     

Depressive symptoms, perceived social support, and prothrombotic measures in patients with venous thromboembolism

Introduction

Psychosocial factors have been associated with both a prothrombotic state and an increased risk of venous thromboembolism (VTE). We examined the relation of depressive symptoms and social support with D-dimer, an integrative measure of enhanced coagulation activity, and several additional prothrombotic measures in patients with VTE.

Methods

We studied 173 patients with a previous deep venous thrombosis and/or pulmonary embolism (mean age ± SD 45 ± 14 years, 55% men). Clinical and lab assessments took place ≥ 3 months after VTE and ≥ 1 month after discontinuation of oral anticoagulants. The patients rated depressive symptoms and social support by validated questionnaires.

Results

After adjusting for sociodemographic and medical covariates, interactions emerged between depressive symptoms and social support for D-dimer (p = 0.012) and aPTT (p = 0.002). As opposed to patients with high levels of social support, those with low levels of social support showed a direct association of depressive symptoms with D-dimer (r = 0.19, p = 0.014) and an inverse relationship with aPTT (r = -0.14, p < 0.09). Depressive symptoms were associated with levels of thrombin-antithrombin complex (r = 0.19, p = 0.016). Greater social support was associated with prolonged aPTT (r = 0.16, p = 0.046). There were no significant associations of depressive symptoms and social support with D-dimer, fibrinogen, FII:C, FV:C, FVII:C, FVIII:C, FX:C, INR, and thrombin time.

Conclusions

Depressive symptoms are associated with enhanced coagulation activity in patients with VTE, particularly so in those who perceive low levels of social support. Conversely, high levels of social support may contribute directly and through buffering the effect of depressive symptoms to attenuated clotting activity in VTE patients.     

Prothrombotic factors and the risk of acute onset non-cardioembolic stroke in young Asian Indians

Introduction

Several prothrombotic factors - both hereditary and acquired - are known to cause stroke. Commonly investigated causes are activated protein C resistance, factor V Leiden mutation, factor VIII levels, prothrombin 20210 G-to-A mutation, coagulation inhibitors such as proteins C and S, and antiphospholipid antibodies such as β₂-glycoprotein.

Objective

The literature on the prevalence of hematological defects pertaining to these variables in the Asian Indian stroke population is limited to a few isolated reports. In the current study we investigate the above-mentioned variables in 120 stroke patients (non-cardioembolic acute-onset stroke) and compare their status with the hematological profile of an equal number of healthy age- and sex-matched controls.

Material and Methods

Plasma and blood leukocytes were collected from all patients and controls for performing hematological assays and molecular tests respectively. The mutations were detected using standard polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) procedures. Statistical analysis was done using SPSS version 12.0.

Results

Factor V Leiden (prevalence 8.3% in patients) and activated protein C resistance (prevalence 19.6% in patients) both showed a high degree of association (P < 0.01) with the disease condition. However, contrary to common expectations, factor V Leiden was observed much less frequently in patients showing activated protein C resistance (10 out of 23; 43.4%) than is commonly observed in the Caucasian population (almost 90%). Post-acute-phase factor VIII levels were also found to be significantly associated with stroke: 125.6 + 21.1% number of profitable positions (NPP) for controls and 136.2 + 28.8% NPP for patients (P = 0.001).

Conclusion

factor V mutations, such as factor V Leiden, may be important risk factors for stroke in an Asian Indian population. Activated protein C resistance has a stronger association with stroke than factor V Leiden and may be caused by other factors such as elevated factor VIII levels in the Asian Indian population apart from factor V Leiden itself.     

Gene polymorphisms and risk of adult early-onset ischemic stroke: A meta-analysis

Introduction

Genetic studies restricted to young adult ischemic stroke patients may help in excluding the potentially confounding variables encountered with advanced age; thus, allowing a more precise risk evaluation derived from the inherited mutations alone. Through meta-analysis, this study was conducted to determine the genetic risk contributed by each susceptibility gene polymorphism, particularly in adult early-onset ischemic stroke patients.

Materials and Methods

Electronic databases were searched for all the case-control studies relating to any candidate genes for ischemic stroke. The range of age was 18-50 years for cases. Fixed or random effects model was used depending on the heterogeneity between studies.

Results

Twenty-six studies were finally included in this meta-analysis; these studies focused on 7 candidate genes. A significant but modest association was identified for 2 polymorphisms, namely, methylenetetrahydrofolate reductase (MTHFR) C677T (OR = 1.44, 95% CI = 1.14-1.80) and apolipoprotein E (ApoE) ε2-4 (OR = 2.53, 95% CI = 1.71-3.73). Although the pooled analysis for platelet glycoprotein Ia (GPIa) C807T showed a positive association (OR = 1.50, 95% CI = 1.10-2.05), the Egger's test indicated the existence of publication bias (t = 5.27, P > |t| = 0.034).

Conclusions

Genetic abnormalities specific to homocysteine and lipid metabolism increase the risk for ischemic stroke at an early age. These data may offer important implications for future genetic association studies for stroke.     

Influence of smoking during pregnancy on haemostasis in healthy full term neonates

Background

Clinical and experimental researches have linked smoking to disturbances of coagulation and fibrinolysis. Several potential mechanisms are incriminated involving inflammation, fibrinogen synthesis and clotting factors. Based on the fact that the majority of tobacco components cross the placental barrier, the objective of our current study is to investigate the influence of smoking during pregnancy on neonatal haemostasis.

Study design

The study was based on a comparative evaluation of coagulation and fibronolysis between healthy full term infants of women who smoked during pregnancy and a control group. Subjects consisted of 39 newborns of smoking and 43 newborns of nonsmoking mothers. Blood samples were obtained shortly after birth and before the administration of vitamin K. Investigation included: PT, INR, aPTT, fibrinogen, coagulation factors II, V, VII, VIII, IX, X, XI, XII, vWillebrand (vWF), protein C and S, APCr, anti-thrombin (AT), t-PA and PAI-1. The independent t- test was used to compare the differences between the values of coagulation and fibrinolytic parameters at the p < 0.05 level.

Results

We discovered a statistically significant decrease in factor II and protein S levels and an elevation in t-PA and factor VIII concentrations in newborns of smoking mothers, without clinical manifestations of altered haemostasis. There were no significant differentiations in other coagulation or fibrinolytic parameters.

Conclusion

The alteration in factor II, protein S, t-PA and factor VIII in neonates exposed in utero to tobacco smoke is not accompanied by loss in the balance between coagulation and fibrinolytic pathways.     

Kynurenines and oxidative status are independently associated with thrombomodulin and von Willebrand factor levels in patients with end-stage renal disease

Introduction

Increased oxidative stress (SOX) is one of the most potent inductors of endothelial dysfunction in end-stage renal disease (ESRD) patients. Kynurenines are the metabolites of tryptophan (TRP) degradation in mammals. However, the role of kynurenines in the function of the endothelium is still not recognized.

Materials and methods

We determined the plasma concentrations of TRP, kynurenine (KYN), 3-hydroxykynurenine (3-HKYN), quinolinic acid (QA); markers of SOX: Cu/Zn superoxide dismutase (Cu/Zn SOD), malondialdehyde (MDA); and endothelial dysfunction markers: thrombomodulin (TM) and von Willebrand factor (vWF) levels in 148 ESRD patients and healthy controls.

Results

TM, vWF, KYN, 3-HKYN and QA levels were significantly elevated in ESRD patients compared to controls. TRP concentrations in uremics were significantly lower than in healthy people. Both dialyzed groups showed a significant increase Cu/Zn SOD and MDA levels compared to controls. TM and vWF were positively associated with kynurenine pathway metabolites: KYN, 3-HKYN, QA (all p < 0.001), and with SOX markers: Cu/Zn SOD (both p < 0.0001) and MDA levels (p < 0.05, and p < 0.0001; respectively) in the whole ESRD group. The positive relationship were between Cu/Zn SOD and KYN (p < 0.010), 3-HKYN and QA levels (both p < 0.0001), whereas MDA was correlated with 3-HKYN and QA concentrations (both p < 0.05). Multiple stepwise regression analysis showed that KYN metabolites and oxidative status were the independent variables significantly associated with increased both TM and vWF levels in uremic patients.

Conclusions

Our study demonstrated that kynurenine metabolites and increased oxidative status are independently and significantly associated with endothelial dysfunction in ESRD patients.     

Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality

Introduction

Disseminated intravascular coagulation (DIC) with an antifibrinolytic phenotype is characterized by microvascular thrombosis leading to poor outcome at the late-stage of trauma. To test the hypothesis that DIC with a fibrinolytic phenotype at an early stage of trauma also contributes to a poor outcome due to severe bleeding, we conducted a retrospective, cohort study.

Materials and Methods

The subjects included 314 consecutive severe trauma patients. A systematic review of medical records of the patients was conducted to provide the base line characteristics and DIC-related variables. The data of these variables were obtained at 4 time points within 24 hr after arrival to the emergency department (ED); Time Point 1, immediately after arrival to the ED to 4 hr after arrival; Time Point 2, 4 to 8 hr after arrival; Time Point 3, 8 to 16 hr after arrival; Time Point 4, 16 to 24 hr after arrival.

Results

Nonsurvivors (87.3%, 48/55) met the Japanese Association for Acute Medicine (JAAM) DIC criteria showing lower fibrinogen levels, a prolonged prothrombin time, and higher fibrin/fibrinogen degradation products (FDP) and D-dimer levels in comparison to those of the 289 survivors. The FDP/D-dimer ratio and lactate level were significantly higher in the nonsurvivors than those of the survivors. Lower fibrinogen levels and higher FDP/D-dimer ratio suggest fibrinogenolysis in DIC of the nonsurvivors. Furthermore a stepwise logistic regression analysis showed that the JAAM DIC score, levels of fibrinogen, FDP and lactate at Time Point 1 are independent predictors of death. Low levels of fibrinogen and high FDP but not D-dimer predict massive bleeding at an early stage of trauma. The optimal cutoff points for the prediction of death and massive bleeding were fibrinogen (1.90, 1.90 g/L) and FDP (35.2, 68.7 mg/L), respectively.

Conclusions

DIC with a fibrinolytic phenotype modified through fibrinogenolysis at an early phase of trauma contributes to poor prognosis due to massive bleeding. Tissue hypoperfusion may be involved in the pathogenesis of this type of DIC.     

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.