Results of the performance verification of the CoaguChek XS system

Background

This is the first paper reporting a performance verification study of a point-of-care (POC) monitor for prothrombin time (PT) testing according to the requirements given in chapter 8 of the International Organization for Standardization (ISO) 17593:2007 standard “Clinical laboratory testing and in vitro medical devices — Requirements for in vitro monitoring systems for self-testing of oral anticoagulant therapy”. The monitor under investigation was the new CoaguChek XS system which is designed for use in patient self testing. Its detection principle is based on the amperometric measurement of the thrombin activity generated by starting the coagulation cascade using a recombinant human thromboplastin.

Methods

The system performance verification study was performed at four study centers using venous and capillary blood samples on two test strip lots. Laboratory testing was performed from corresponding frozen plasma samples with six commercial thromboplastins. Samples from 73 normal donors and 297 patients on oral anticoagulation therapy were collected. Results were assessed using a refined data set of 260 subjects according to the ISO 17593:2007 standard.

Results

Each of the two test strip lots met the acceptance criteria of ISO 17593:2007 versus all thromboplastins (bias − 0.19 to 0.18 INR; > 97% of data within accuracy limits). The coefficient of variation for imprecision of the PT determinations in INR ranged from 2.0% to 3.2% in venous, and from 2.9% to 4.0% in capillary blood testing. Capillary versus venous INR data showed agreement of results with regression lines equal to the line of identity.

Conclusion

The new system demonstrated a high level of trueness and accuracy, and low imprecision in INR testing. It can be concluded that the CoaguChek XS system complies with the requirements in chapter 8 of the ISO standard 17593:2007.     

Haemostatic profile of full-term, healthy, small for gestational age neonates

Background

Small for Gestational Age (SGA) neonates often appear with haemostatic alterations, principally due to hepatic dysfunction that results from chronic intrauterine hypoxia. Polycythaemia and thrombocytopenia are common findings in this neonatal population.

Study design

We performed a comparison of coagulation, natural inhibitors and fibrinolysis between SGA and Appropriate for Gestational Age (AGA) infants born full term [gestational age (G.A.) > 37 weeks]. Study population consisted of 188 healthy newborns, 90 of whom were SGA (62 females and 28 males), while the rest were the control group (44 females and 54 males). Blood samples were obtained within 30 minutes following 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 factor, protein C and free protein S, antithrombin (AT), APCR, tPA and PAI-1. The independent t-test was used to compare the differences between the values of haemostatic parameters.

Results

Statistical analysis revealed a significant prolongation in PT, INR, elevated levels of tPA (p < 0.015, 0.01 and 0.002 respectively) and a decrease in the values of XII and free protein S (p < 0.045 and 0.007 respectively) in SGA full term neonates. The two groups had similar demographic characteristics (except birth weight), without significant differences in the values of other haemostatic parameters.

Conclusions

Despite of statistically significant differences in PT, INR, values of tPA, XII and free protein S, levels of haemostatic factors range within laboratory references for healthy full term newborns. These findings were not accompanied with clinical manifestations of altered haemostasis.     

The clinical significance of differences between point-of-care and laboratory INR methods in over-anticoagulated patients

Introduction

Patients receiving warfarin are at increased risk of bleeding when their International Normalised Ratio (INR) > 4.5. Although not standardised above 4.5 the INR is measured in over-anticoagulated patients, consequently we have examined the reliability of INR results ≥ 4.5. We assessed: the relationship between different prothrombin time systems for INRs > 4.5; the relationships between the INR and levels of vitamin K-dependent coagulation factors (VKD-CF) and thrombin generation test (TGT) parameters; and the impact that variation in results would have on warfarin dosing.

Methods

INRs were performed using a CoaguChek XS Plus point-of-care (POC) device (measuring range 0.6-8.0). For POC INRs ≥ 4.5, laboratory INRs were also measured using a recombinant tissue factor (rTF) and a rabbit brain (RBT) thromboplastin.

Results

There was good correlation between POC (INR ≥ 4.5, < 8.0) and Lab INRs (rTF n = 154, rs = 0.87, p < 0.0001; RBT n = 102, rs = 0.76, p < 0.0001); and significant correlations between each of the VKD-CF and the INR, the strongest being with FVII (POC INR rs = -0.53 p < 0.0001; Lab rTF-INR rs = -0.70 p < 0.0001). TGT peak thrombin and ETP also showed good correlations with INR values (R² > 0.71). Using POC and Lab rTF-INR, 109/154 (71%), or POC and Lab RBT-INR 75/102 (74%) results exhibited dosage concordance and/or were within 0.5 INR units. In the remaining patients variation in warfarin dosing was generally slight.

Conclusions

Our data suggest that CoaguChek XS Plus INRs > 4.5 and < 8.0 are comparable to laboratory INRs (both methods) and it is probably unnecessary to perform laboratory INRs for clinical management of patients with INRs > 4.5 including those > 8.0.     

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.     

Accuracy and clinical usefulness of the CoaguChek S and XS Point of Care devices when starting warfarin in a hospital outreach setting

Objective

To assess clinical usefulness of CoaguChek S and XS monitors to measure International Normalised Ratio (INR) when starting warfarin in community patients.

Methods

INR in consecutive patients starting warfarin plus enoxaparin was measured in the laboratory and on capillary blood at home using CoaguChek S or XS point of care (POC) devices. INR was measured daily until > 2.0 for 2 consecutive readings. Linear regression and Bland Altman plots were derived to compare POC with laboratory INR. Percentages of POC measurements within 0.5 and 0.8 units of laboratory INR <2.0, 2.0-3.5 and > 3.5 were calculated. Clinical utility was assessed using previously reported criteria.

Results

200 CoaguChek S and 337 CoaguChek XS results were obtained from 57 and 98 patients respectively and paired with laboratory values. Correlation was acceptable between CoaguChek S and laboratory INRs (r² = 0.7732), and excellent between CoaguChek XS and laboratory INRs (r² = 0.9514). Bland-Altman plots showed an increasing difference between laboratory INR above 3.0 for CoaguChek S INRs but no systematic bias with increasing CoaguChek XS INRs. 83.5% of CoaguChek S and 93.5% of CoaguChek XS INRs were within 0.5 units of laboratory INR. 90% of CoaguChek S and 99.4% of the CoaguChek XS INRs were within 0.8 units of laboratory INR. Clinical agreement occurred in 89% and 99.7% of cases by expanded criteria and 82% and 99.4% of cases by narrow criteria when using CoaguChek S and CoaguChek XS respectively.

Conclusions

The CoaguChek XS is suitable for outpatient INR monitoring when starting warfarin.     

Shear-induced global thrombosis test of native blood: Pivotal role of ADP allows monitoring of P2Y12 antagonist therapy

Background

It is claimed that in shear-induced platelet function tests, shear-stress is the sole agonist causing platelet activation and resultant thrombosis. However, the fact that red blood cells (RBC) are essential to achieve platelet aggregation in these tests supports recent evidence that ADP makes an important contribution to shear-induced platelet reaction.

Aim

To establish the role of ADP in shear-induced thrombosis, and investigate whether a shear-induced thrombosis test can assess ADP-receptor (P2Y12) antagonist medication.

Methods

Blood from healthy volunteers was tested using the Global Thrombosis Test (GTT), before and after clopidogrel. To investigate the importance of contact of blood with plastic, the reactive part of the tube was primed with saline. We also investigated the effect of priming the tube with water, to cause localised haemolysis and ADP release.

Results

Saline-priming prolonged occlusion times (OT) by 25% (p < 0.01) confirming ADP release from platelets and RBC as a result of contact. Water-priming shortened OT, accelerating the thrombotic reaction (accelerated GTT; aGTT) (OT 379 vs. 177s, p < 0.01). Clopidogrel increased OT (379 vs. 477s, p < 0.01), preventing the shortening of aGTT-OT (177 vs. 362s, pre- and post-clopidogrel; p < 0.01).

Conclusion

In addition to thrombin formation, ADP released from platelets and RBC in native blood subjected to high shear-stress makes an important contribution to the resultant thrombotic occlusion. The described aGTT sensitively detected the effect of clopidogrel and thus seems suitable for monitoring and individualizing ADP-receptor antagonist therapy. Parallel measurement of GTT and aGTT would allow assessment of both global thrombotic status and response to P2Y12 antagonist therapy.     

Thrombin-activatable fibrinolysis inhibitor genetic polymorphisms as markers of the type of acute coronary syndrome

Introduction

In patients with coronary disease at risk of acute coronary events it is unclear which biological factors could predict the type of acute coronary syndrome clinical presentation. The aim of the study was to investigate the role of genetic polymorphisms in key proteins in fibrinolysis in the type of acute coronary syndrome.

Materials and methods

248 patients with acute coronary syndrome (unstable angina or myocardial infarction) (77% male, mean age 60.75 SD 13.30 years) were prospectively recruited. PAI-1 (type-1 plasminogen activator inhibitor) 4G/5G and TAFI (thrombin-activatable fibrinolysis inhibitor) Ala147Thr, C+1542G, and Thr325Ile polymorphisms were determined by PCR.

Results

147 (59.3%) patients presented with ST-segment elevation acute coronary syndrome (all Q-wave myocardial infarction), and 101 (40.7%) with non-ST-elevation acute coronary syndrome (52 non-Q wave myocardial infarction, and 49 unstable angina). Homozygous TAFI + 1542G and TAFI 325Ile genotypes were less prevalent in patients with ST elevation acute coronary syndrome (p < 0.001, OR: 0.22, 95% CI 0.10-0.50 and p < 0.001, OR: 0.25, 95% CI 0.11-0.55, respectively). There were no differences in TAFI Ala147Thr or PAI genotype distribution between ST elevation and non-ST elevation acute coronary syndrome. In the multivariate analysis including clinical variables, the best model for ST elevation acute coronary syndrome included TAFI + 1542GG (p < 0.001, OR: 0.17, 95% CI 0.07-0.30), age (in years, p < 0.005, OR: 0.97, 95% CI 0.94-0.98) and dyslipidemia (p < 0.005, OR: 2.33, 95% CI 1.42-3.80).

Conclusion

TAFI polymorphism C+1542G and Thr325/Ile are related to the type of acute coronary syndrome. Patients with coronary disease would benefit from individualized cardiovascular prophylaxis based on genetic risk.     

Impact of P2Y12 Inhibitory Effects Induced by Clopidogrel on Platelet Procoagulant Activity in Type 2 Diabetes Mellitus Patients

Introduction

Type 2 diabetes mellitus (T2DM) patients have a variable response profile to the P2Y₁₂ receptor antagonist clopidogrel. P2Y₁₂ receptor signalling promotes platelet procoagulant activity. The aim of this study was to determine if T2DM patients with suboptimal clopidogrel response have greater platelet procoagulant activity compared with optimal responders and evaluate if this can be modulated by enhancing P2Y₁₂ receptor inhibition.

Materials and Methods

A total of 50 T2DM patients in a steady state phase of clopidogrel therapy were studied. Suboptimal responders were randomly assigned to standard (75 mg) or high (150 mg) clopidogrel maintenance therapy for one-month. Afterwards, all patients resumed standard therapy. Platelet procoagulant activity assessed by thrombin-induced platelet-fibrin clot formation using thrombelastography (TEG) was determined at baseline, one-month post-randomization, and one-month after resuming standard therapy.

Results

In the overall study population, the reaction time (R), a measure of time to initial thrombin induced platelet-fibrin clot formation, and the time to maximum rate of thrombin generation (TMRTG) values were 6.3 ± 1.7 and 7.6 ± 1.9 minutes, respectively. Suboptimal clopidogrel responders (n = 30) had acceleration of R (p = 0.002) and TMRTG (p = 0.002) compared to optimal responders (n = 20). Suboptimal clopidogrel responders treated with a 150 mg dose showed prolongation of R (p = 0.0001) and TMRTG (p < 0.0001), which returned to baseline values after resuming standard dosage. No differences were observed among patients randomized to 75 mg.

Conclusions

T2DM patients with suboptimal clopidogrel response have enhanced platelet procoagulant activity compared to patients with optimal response, which can be down-regulated by more potent platelet P2Y₁₂ inhibition using high clopidogrel maintenance dosing.     

Association of the -757T>C polymorphism in the CRP gene with circulating C-reactive protein levels and carotid atherosclerosis

Introduction

C-reactive protein (CRP) is an inflammatory protein that may play a role in the pathogenesis of atherosclerosis. CRP gene single nucleotide polymorphisms (SNPs) have been shown to be associated with CRP concentration; however, their independent effect on atherosclerosis has not been yet established. We aimed to determine whether the 5′-flanking -757T>C CRP gene polymorphism is associated with CRP concentration and carotid atherosclerosis.

Methods

We genotyped the -757T>C CRP gene SNP and determined the concentration of serum CRP, the intima-media thickness (IMT) of the common carotid artery and the existence of plaque/s in 612 apparently healthy men and women aged 66 ± 10 years.

Results

Carriers of the CRP -757C allele presented with higher IMT and higher CRP concentrations (p = 0.002, p = 0.042, respectively). After adjustment for vascular risk factors, linear regression analysis showed an independent effect of CRP -757C allele on carotid IMT, beyond serum CRP concentrations. This SNP was also associated with carotid plaque occurrence (O.R. 1.74, 95% CI 1.1-2.77, p = 0.002).

Conclusions

The present study provides evidence that a genetic variant of CRP gene is associated with carotid atherosclerosis, independently of traditional vascular risk factors. Further large-scale genomic studies are required, which may identify the genetic vulnerable subjects to develop atherosclerosis.     

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.     

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.     

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.     

Platelet inhibition assessed with VerifyNow, flow cytometry and PlateletMapping in patients undergoing heart surgery

Introduction

A substantial number of patients with coronary artery disease undergo cardiac surgery within five days of discontinuing anti-platelet treatment with aspirin and clopidogrel. The aims of this study were to describe the degree of platelet inhibition in patients with dual anti-platelet treatment scheduled for coronary artery bypass graft (CABG) surgery and to investigate whether the measured platelet inhibition correlated to intra- and postoperative risk for bleeding and transfusion requirements.

Material and Methods

Sixty patients were included. Platelet inhibition was analysed with flow cytometry including phosphorylation status of the vasodilator-stimulated phosphoprotein (VASP-assay) and two bed-side analyzers, VerifyNow-System and PlateletMapping, a modified thrombelastograph. All 60 patients were analysed with VerifyNow and PlateletMapping, and 48 were analysed with flow cytometry and VASP-assay.

Results

There was a correlation between the ADP-receptor inhibition as measured by VASP-assay and VerifyNowP2Y₁₂ (r = - 0.29, p < 0.05), and between VASP-assay and the expression of P-selectin (r = 0.29, p < 0.05) as measured by flow cytometry when platelets were stimulated with 5 µM ADP. VerifyNowP2Y₁₂ was the only measurement of platelet inhibition correlated to total blood loss (Spearman r = 0.29, p = 0.03) and red blood cell transfusion (Spearman r = 0.43, p < 0.01) requirements, although this might be confounded by aprotinin treatment.

Conclusion

We found a modest agreement between the methods for preoperative platelet inhibition, though not for PlateletMapping-MA_ADP. There was a correlation between preoperative platelet inhibition measured by VerifyNowP2Y₁₂ and surgical blood loss or transfusion requirements. However, for the individual patient, preoperative use of VerifyNowP2Y₁₂ as an instrument to decide bleeding and transfusion risk does not seem helpful.     

Comparison between CoaguChek S- and Owren-type prothrombin time assay for monitoring anticoagulant therapy

INTRODUCTION: Anticoagulation therapy with warfarin is monitored by the prothrombin time (PT) assay. The PT is standardized using international normalized ratios (INRs). By keeping the INR within specific values, it is possible to reduce potential complications from the treatment. To facilitate the PT monitoring, point-of-care devices suitable for capillary whole blood measurements have been developed. The aims of this study were to compare the INR values obtained by such a device, CoaguChek S, with those obtained from the Owren-type PT assay and to evaluate the differences seen. MATERIALS AND METHODS: In 351 consecutive warfarin-treated patients, INR was measured in capillary whole blood samples with CoaguChek S and was compared to venous plasma samples analyzed with the Owren PT method. Sixty-nine of these patients, including those deviating the most between the methods, were further evaluated according to levels of factor II (prothrombin), factor V, factor VII, factor X, fibrinogen, activated partial thromboplastin time (aPTT) and antiphospholipid antibodies. RESULTS: The results from CoaguChek S produced a correlation coefficient of 0.81 to the Owren-type PT assay and a concordance of 85.2%. Factor V and fibrinogen correlated significantly (p<0.05) to the degree of deviation between the methods. The presence of antiphospholipid antibodies did not influence the degree of deviation between the two methods. CONCLUSIONS: INR analysis of whole blood with CoaguChek S is comparable with INR measured in plasma with Owren chemistry. The activities of factor V and fibrinogen contribute to the deviation seen between the methods. Differences in sensitivity to antiphospholipid antibodies could not be demonstrated.     

Risk factors for unfavorable clinical outcome in patients with documented heparin-induced thrombocytopenia

Background

Prognostic factors for unfavorable clinical outcome in patients with heparin-induced thrombocytopenia (HIT) are largely unknown.

Design and methods

In this multicenter, retrospective, case-control study, all HIT patients were treated with danaparoid. Study cases were HIT patients with an unfavorable clinical outcome. Controls were HIT patients who were not study cases. Unfavorable clinical outcome was defined as the occurrence of at least one of the following clinical events: death within 60 days after HIT start date, or venous or arterial thromboembolism, amputation, major bleeding, or disseminated intra-vascular coagulation between 48 hours and 60 days after HIT start date.

Results

Compared with controls (n = 65), thrombotic episodes within 48 hours of HIT start date were more frequent (59.2% versus 32.3%; p = 0.004), the median time between HIT start date and initiation of danaparoid infusion was longer (3.0 versus 1.0 days; p = 0.001), and this treatment was more frequently underdosed (43.8% versus 18.8%; p = 0.004) in study cases (n = 49). Upon multivariate analysis, all these three parameters were significant predictive factors for unfavorable clinical outcome. The adjusted odds ratios [95% confidence interval] were 6.6 [2.5-17.3] for time between HIT start date and danaparoid initiation over 48 hours, 4.3 [1.5-12.0] for danaparoid underdosing, and 3.2 [1.3-8.0] for presence of a thromboembolic episode at HIT start date.

Conclusions

This study supports the recommendations concerning the management of HIT patients, namely discontinuation of all heparin administration once the diagnosis is suspected and prompt initiation of an alternative anticoagulant drug with a strict adherence to doses specifically recommended for these patients.     

Peri-procedural anticoagulation management of mechanical prosthetic heart valve patients

Introduction

To estimate the three-month cumulative incidence of thromboembolism and bleeding among mechanical heart valve (MHV) patients receiving peri-procedural anticoagulation management, consecutive MHV patients referred to the Mayo Clinic Thrombophilia Center for peri-procedural anticoagulation management over the seven-year period, 1997-2003, were followed for three months for thromboembolism, bleeding and vital status.

Materials and Methods

Warfarin was stopped 4-5 days prior to the procedure, and re-started after the procedure as soon as hemostasis was assured. The decision to provide bridging therapy with low molecular weight (LMWH) or unfractionated (UFH) heparin was individualized and based on the estimated risks of TE and bleeding.

Results

556 MHV patients (372 aortic only, 136 mitral only, 48 with multiple valves) underwent 580 procedures. The three-month cumulative incidence of thromboembolism was 0.9% which included: cerebral ischemia (n = 3), unstable angina (n = 1), acute myocardial infarction (n = 1). None were fatal. The cumulative incidence of major bleeding was 3.6% and fatal in 0.2%. The incidence of major bleeding events did not differ by postoperative anticoagulant strategy whether LMWH (3.7%), UFH (6.1%), or no heparin (2.4%) was used (p = 0.26).

Conclusions

The three-month cumulative incidence of thromboembolism among MHV patients in whom anticoagulation is temporarily interrupted for an invasive procedure is low. Whereas bleeding exceeds thromboembolic complications, our current practice is to restart warfarin as soon as possible post-procedure. Post-procedural heparin use is reserved for patients with the highest thromboembolic risk (mitral MHV, multiple MHVs, MHV with prior stroke or atrial fibrillation) waiting at least 48 hours before initiating.     

Differential alteration of automatic semantic processing in treated patients affected by bipolar mania and schizophrenia: an N400 study

Background

Various formal thought disorders are presented as symptoms by manic patients including pressure of speech, flight of ideas, and more complex speech with strong emotional components. N400 is the event-related potential, in which amplitude is suggested to be a general index of efforts to retrieve stored semantic context, which depends on the stored representation itself and the retrieval cue stimuli. The present study examines N400 components induced by a word-matching task in manic patients, and compare these responses to those induced by the task in schizophrenia and healthy controls.

Methods

Twenty manic patients, twenty schizophrenic patients, and twenty healthy controls performed the word-matching task, in which they were presented with 120 (60 congruent and 60 incongruent) word pairs, they were instructed to discriminate whether each word pair was congruent or incongruent. During the task, we recorded the electroencephalogram.

Results

Reaction time analysis revealed a main effect for priming, in which reaction times were longer in response to incongruent words than to congruent words in all three participant groups (F = 43.1, p < 0.001) with no group effects (F = 2.3, p = 0.11). N400 analysis showed the main effect for priming (F = 30.2, p < 0.001), for group (F = 5.0, p = 0.01), and the interaction of priming × group (F = 4.6, p = 0.02). Post-hoc analysis of this interaction revealed larger N400 amplitudes to congruent words in manic patients (F = 4.0, p = 0.02) and smaller N400 to incongruent words in schizophrenic patients than in other groups (F = 6.1, p = 0.004). No correlations were found between N400 and symptom severity within patient groups.

Conclusions

These findings suggest that priming effects of contextually related word pairs are decreased in patients with bipolar mania, whereas priming N400 responses of contextually unrelated word pairs are increased in schizophrenia. This may be the neurophysiological evidence of abnormal automatic semantic processing in patients with bipolar mania, and it also reflects a qualitative difference in thought and speech disorders between bipolar manic and schizophrenia.     

The international normalized ratio according to Owren in liver disease: Interlaboratory assessment and determination of international sensitivity index

Introduction

The international normalized ratio (INR) is used to prioritize liver disease patients for transplantation. Previous studies have shown high interlaboratory variability in Quick-based INR determinations in samples of patients with liver disease. We assessed Owren-based INR reagents for analyzing INR in patients with liver disease. Further, we determined the difference between international sensitivity index (ISI) for patients on vitamin K antagonists (ISI_VKA) and ISI for patients with liver disease (ISI_liver).

Patients and Methods

Twenty patients with liver disease were included, 10 with INR 1.8-3.6 (group A1) and 10 with INR 1.2-1.5 (group C1). Plasma from these patients was analyzed for Owren-based INR in eight Swedish laboratories using either of following reagents: SPA +, Owrens PT or Nycotest PT. To determine ISI liver, the reference thromboplastin RBT/05 and additional 41 patients with liver disease and 20 normal controls were included. ISI_VKA was determined according to the WHO procedure. The difference between the ISI_VKA and ISI_liver was calculated.

Results

The coefficients of variance for the Owren based INR methods were 6.2% in group A1, 3.9 % in group C1 and 5.3% for all patients. The difference between ISI_VKA and ISI_liver were -0.4%, -0.7% and -0.2% for SPA +, Owrens PT and Nycotest PT respectively.

Conclusions

Interlaboratory variation in INR analyses according to Owren in patients with liver disease is low and the difference between ISI_VKA and ISI_liver is below 10% with this method. ISI_VKA can therefore be used in the INR calibration, for the Owren reagents studied, when analyzing plasma from patients with liver disease.     

Point-of-care (POCT) prothrombin time monitors: is a periodical control of their performance useful?

Introduction

Point-of-care testing (POCT) prothrombin time monitors are now widely used to monitor oral anticoagulant treatment. Although portable coagulometers are extremely easy to use, checking the quality of their performance presents some difficulties.

Materials and Methods

The aims of this study were to investigate on a quarterly basis the performance of 95 Coagucheck S assigned to 99 anticoagulated patients at home. This was done checking the monitors versus a reference coagulometer in the laboratory at our Thrombosis Centre (TC). The other aims were to carry out an external quality assessment employing different sets of INR certified plasmas with 5 different ranges of anticoagulation and to assess the performance of the different lots of strips employed by the patients during the study.

Results

No difference between the PT INR obtained with both the systems at the first quarterly check was noted but a significant difference was found when the two systems were compared at the second and third quarterly checks. The Bland-Altman test showed increased disagreement between the first and the third controls. The percentage of INR values that showed a difference of more or less than 0.5 INR units in the PT values performed with both the systems was: 1.0% (first control), 7.5% (second control) and 11.5% (third control) (Chi-Square: 8.315, p = 0.0156). Lots with differences higher than 10% in terms of ± 0.5 INR Units at the first, second and third controls were 16%, 20.8% and 61%, respectively. Seven monitors (7.3%) failed to test one or two of the INR certified plasmas of one set but performed well using a second set of plasmas. Three monitors (3.1%) failed to test two sets of plasmas but performed well using a different lot of strips (from 279A to 483A). One monitor (1%) gave unsatisfactory results with different sets of plasmas and strips. All the other PT INR obtained with the monitors fell well within the different ranges of the INR certified plasmas.

Conclusions

Anticoagulated patient in self-testing or self-management should periodically bring their portable coagulometer to a reference Thrombosis Centre especially when the lot of strips have to be changed. The role of Thrombosis Centre appears therefore crucial in this regard.     

Level of agreement between laboratory and point-of-care prothrombin time before and after cardiopulmonary bypass in cardiac surgery

Background

Hemostasis monitoring in cardiac surgery could benefit from an easy to use and fast point-of-care coagulation monitor, since routine laboratory tests have a delay of 30–45 minutes. This study investigated the level of agreement between the point-of-care prothrombin time (PT) with central laboratory PT before and after cardiopulmonary bypass.

Methods

Bland Altman and error grid analysis were used to analyze the agreement between the point-of-care Coaguchek XS Pro device (POC-PT) and the central laboratory prothrombin time (LAB-PT) before cardiopulmonary bypass (CPB) and 3 minutes after protamine administration. Prothrombin times were expressed in international normalized ratios (INR).

Results

The average POC-PT and LAB-PT values of 73 patients were 1.06 ± 0.14 and 1.09 ± 0.13 (P = 0.10) before CPB. POC-PT measurements before CPB showed a good agreement with the LAB-PT, with a bias of − 0.02 ± 0.07 INR and 94% of the values being represented in the clinical acceptable zone of error grid analysis. The mean POC-PT 3 minutes after protamine administration was significantly lower than the LAB-PT (1.35 ± 0.12 vs. 1.70 ± 0.18; P < 0.001). The PT at 3 minutes after protamine administration showed a bias of 0.36 ± 0.14, and 82% of the values were located outside of the clinical acceptable zone in the error grid analysis.

Conclusions

Point-of-care prothrombin time testing was in concordance with conventional laboratory PT prior to cardiopulmonary bypass. At 3 minutes following protamine administration, PT values of the point-of-care device were structurally lower than the laboratory PT values, leading to a disagreement between both tests at that time point.