International collaborative study for the calibration of a proposed international standard for thromboplastin, rabbit, plain

BACKGROUND: A preparation of rabbit brain thromboplastin, provisionally coded 04/162, is proposed as a candidate for the World Health Organization (WHO) International Standard (IS) for thromboplastin (rabbit, plain), meant to replace the IS coded RBT/90 (rabbit, plain), stocks of which are now exhausted. RESULTS: The preparation was calibrated in an international collaborative study involving 21 laboratories from 13 countries and the calibration was performed against the existing WHO-IS (i.e. rTF/95 and OBT/79) and other Certified Reference Materials from the Institute for Reference Materials and Measurements of the European Commission (i.e. CRM149 S) and from the European Action on Anticoagulation (i.e. EUTHR-01). An additional candidate rabbit brain thromboplastin coded as 04/106 was also included in the study. On the basis of predefined criteria (the within- and between-laboratory precision of the calibration and the conformity to the calibration model), 04/162 was the preferred candidate. CONCLUSIONS: The assigned International Sensitivity Index value was 1.15 and the inter-laboratory SD and coefficient of variation were 0.057% and 4.9%, respectively.     

International multicenter international sensitivity index (ISI) calibration of a new human tissue factor thromboplastin reagent derived from cultured human cells

Summary.  The international sensitivity index (ISI) of the first working standard of Simplastin HTF, a new human tissue factor thromboplastin derived from cultured human cells, has been assessed in a calibration exercise in two Canadian and five European laboratories. Calibrations against international reference preparations (IRP) were performed for the manual method and six types of automated coagulometers that cover the majority of clotting endpoint principles in routine use. The ISI was method-dependent and varied between 1.03 and 1.29 when calibrated against rTF/95 (human IRP). The ISI was also dependent on the route of calibration. Compared with calibration against rTF/95, the ISIs obtained by calibration against RBT/90 (rabbit IRP) were on average 4.4% higher ( P  < 0.005). Considering the principle of 'like vs. like', the ISIs obtained by calibration against rTF/95 should be preferred.     

Use of lyophilized calibrant plasmas for simplified international normalized ratio determination with a human tissue factor thromboplastin reagent derived from cultured human cells

BACKGROUND: For monitoring of treatment with oral anticoagulants, the clotting time obtained in the prothrombin time (PT) test is transformed to the International Normalized Ratio (INR) with use of a system-specific International Sensitivity Index (ISI). The calibrant plasma procedure (CPP) is an alternative approach to INR calculation based on the use of a set of lyophilized plasmas with assigned INRs. METHODS: With the CPP, a linear relationship is established between log(PT) and log(INR), using orthogonal regression. CPP was validated for Simplastin HTF, a new human tissue factor reagent derived from cultured human cells. CPP precision was assessed as the CV of the slope of the regression line. The accuracy of the CPP was determined by comparing the INR obtained with the CPP with that obtained with the established ISI-based reference method. INRs of the calibrants were assigned by different routes: by manufacturer (consensus labeling) or by use of Simplastin HTF or International Reference Preparations (IRPs; rTF/95 or RBT/90). RESULTS: The mean CV of the CPP regression slope ranged from 1.0% (Simplastin HTF reagent-specific INR) to 2.4% (INR assigned with rTF/95). INRs calculated with the CPP were similar to those obtained with the reference method, but when the routes for assigning INRs to the calibrant plasmas were compared, the mean difference in INR between CPP and the reference method was smaller with Simplastin HTF reagent-specific values. In several (but not all) cases, this difference was significant (P <0.05, t-test). CONCLUSION: CPP can be used for local INR determination, but better precision and accuracy are obtained with reagent-specific INRs compared with INR assignment by consensus labeling or IRP.     

Properties of recombinant human thromboplastin that determine the International Sensitivity Index (ISI)

Prothrombin Time (PT) clotting tests are widely used to monitor oral anticoagulation therapy and to screen for clotting factor deficiencies. The active ingredient in PT reagents (thromboplastins) is tissue factor, the integral membrane protein that triggers the clotting cascade through the extrinsic pathway. Several years ago, a system for calibrating and using thromboplastin reagents, known as the International Sensitivity Index (ISI) and the International Normalized Ratio (INR), was developed to standardize monitoring of oral anticoagulant therapy. The ISI/INR method, while revolutionizing the monitoring of coumarin therapy, has been criticized for a number of perceived shortcomings. We have undertaken a series of studies aimed at achieving a detailed understanding of which parameters influence the ISI values of thromboplastin reagents, with an ultimate goal of creating 'designer thromboplastins' whose sensitivities to the various clotting factors can be individually tailored. In this study, we demonstrate that ISI values of thromboplastin reagents based on relipidated, recombinant human tissue factor can be controlled by a combination of changes in the phospholipid content (in particular, the levels of phosphatidylserine and phosphatidylethanolamine) and ionic strength. The sensitivity of a given thromboplastin reagent can be increased (i.e. its ISI value decreased) by decreasing the content of phosphatidylserine and/or increasing the ionic strength. The molar ratio of phospholipid to tissue factor, on the other hand, had essentially no impact on ISI value.     

Extended International Normalized Ratio testing intervals for warfarin‐treated patients

Essentials

• Warfarin typically requires International Normalized Ratio (INR) testing at least every 4 weeks.
• We implemented extended INR testing for stable warfarin patients in six anticoagulation clinics.
• Use of extended INR testing increased from 41.8% to 69.3% over the 3 year study.
• Use of extended INR testing appeared safe and effective.

Summary

Background

A previous single‐center randomized trial suggested that patients with stable International Normalized Ratio (INR) values could safely receive INR testing as infrequently as every 12 weeks.

Objective

To test the success of implementation of an extended INR testing interval for stable warfarin patients in a practice‐based, multicenter collaborative of anticoagulation clinics.

Methods

At six anticoagulation clinics, patients were identified as being eligible for extended INR testing on the basis of prior INR value stability and minimal warfarin dose changes between 2014 and 2016. We assessed the frequency with which anticoagulation clinic providers recommended an extended INR testing interval (> 5 weeks) to eligible patients. We also explored safety outcomes for eligible patients, including next INR values, bleeding events, and emergency department visits.

Results

At least one eligible period for extended INR testing was identified in 890 of 3362 (26.5%) warfarin‐treated patients. Overall, the use of extended INR testing in eligible patients increased from 41.8% in the first quarter of 2014 to 69.3% in the fourth quarter of 2016. The number of subsequent out‐of‐range next INR values were similar between eligible patients who did and did not have an extended INR testing interval (27.3% versus 28.4%, respectively). The numbers of major bleeding events were not different between the two groups, but rates of clinically relevant non‐major bleeding (0.02 per 100 patient‐years versus 0.09 per 100 patient‐years) and emergency department visits (0.07 per 100 patient‐years versus 0.19 per 100 patient‐years) were lower for eligible patients with extended INR testing intervals than for those with non‐extended INR testing intervals.

Conclusions

Extended INR testing for stable warfarin patients can be successfully and safely implemented in diverse, practice‐based anticoagulation clinic settings.

     

Variability of cut‐off values for the detection of lupus anticoagulants: results of an international multicenter multiplatform study

Essentials

• Between‐lab variations of cut‐off values in lupus anticoagulant detection are unknown.
• Cut‐off values were calculated in 11 labs each testing plasma from 120 donors with 3 platforms.
• Major variation was observed even within the same platform.
• Cut‐off values determined in different labs are not interchangeable.

Summary

Background

Cut‐off values for interpretation of lupus anticoagulant (LA) detection are poorly investigated.

Aims

(i) To assess whether results from healthy donors were normally distributed and (ii) the between‐laboratories differences in cut‐off values for screening, mixing and LA confirmation when calculated as 99th or 95th centiles, and (iii) to assess their impact on the detection rate for LA.

Methods

Each of 11 laboratories using one of the three widely used commercial platforms for LA detection was asked to collect plasmas from 120 healthy donors and to perform screening, mixing and LA confirmation with two methods (activated partial thromboplastin time [APTT] and dilute Russell viper venom [dRVV]). A common set of LA‐positive or LA‐negative freeze‐dried plasmas was used to assess the LA detection rate. Results were centralized (Milano) for statistical analysis.

Results and conclusions

(i) Clotting times or ratios for healthy subjects were not normally distributed in the majority of cases. The take‐home message is that cut‐off values should be determined preferably by the non‐parametric method based on centiles. (ii) There were relatively large inter‐laboratory cut‐off variations even within the same platform and the variability was marginally attenuated when results were expressed as ratios (test‐to‐normal pooled plasma). The take‐home message is that cut‐off values should be determined locally. (iii) There were differences between cut‐off values calculated as 99th or 95th centiles that translate into a different LA detection rate (the lower the centile the greater the detection rate). The take‐home message is that cut‐off values determined as the 95th centile allow a better LA detection rate.     

凝血活酶参考品国际敏感度指数的标定

目的标定出凝血活酶参考品（ＷＲＰ），为国内凝血活酶产品国际敏感度指数（ＩＳＩ）的标定提供依据。方法以凝血活酶国际参考品为标准（ＩＲＰ），按照世界卫生组织（ＷＨＯ）推荐的凝血活酶国际参考品的使用方法进行测定，计算出被标定凝血活酶参考品的ＩＳＩ值和标定ＩＳＩ值的变异系数（ＣＶ）。结果标出的凝血活酶参考品的ＩＳＩ值为１．３５，标定ＩＳＩ值的ＣＶ为４．３％。符合ＷＨＯ的要求（ＣＶ≤５％）。结论用ＩＲＰ标定的凝血活酶参考品可作为国内凝血活酶试剂ＩＳＩ值标定的标准。     

Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics,safety, and tolerability

Essentials

• Dabigatran etexilate may provide a new treatment option for pediatric venous thromboembolism.
• Children aged 1 to < 12 years were given dabigatran etexilate in an open‐label, single‐arm study.
• The pharmacokinetic–pharmacodynamic relationship was similar to that seen in adult patients.
• There were no serious adverse events, bleeding events or recurrent venous thromboembolism.

Summary

Background

The current standard‐of‐care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option.

Objectives

To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of a DE oral liquid formulation (OLF) in pediatric patients with VTE.

Patients/Methods

Patients who had completed planned treatment with low molecular weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2 to < 12 years and 1 to < 2 years), and received a DE OLF based on an age‐adjusted and weight‐adjusted nomogram. Originally, patients were to receive a DE OLF twice daily for 3 days, but the protocol was amended to a single dose on day 1. The primary endpoints were pharmacokinetics/pharmacodynamics‐related: plasma concentrations of DE and its metabolites; activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and dilute thrombin time (dTT); and pharmacokinetic (PK)–pharmacodynamic (PD) correlation. Safety endpoints included incidence rates of bleeding events and all other adverse events (AEs).

Results

Eighteen patients entered the study and received the DE OLF (an exposure equivalent to a dose of 150 mg twice daily in adults). The projected steady‐state dabigatran trough concentrations were largely comparable between pediatric patients and adults. The PK/PD relationship was linear for ECT and dTT, and non‐linear for APTT. No serious or severe AEs, bleeding events, or recurrent VTEs were reported. Mild AEs were reported in three patients in the single‐dose group (screening period) and in one patient in the multiple‐dose group (on‐treatment period).

Conclusion

The current study supports the further evaluation of DE OLFs in pediatric patients with VTE.     

Heparin–protamine balance after neonatal cardiopulmonary bypass surgery

Essentials

• Heparin‐protamine balance (HPB) modulates bleeding after neonatal cardiopulmonary bypass (CPB).
• HPB was examined in 44 neonates undergoing CPB.
• Post‐operative bleeding occurred in 36% and heparin rebound in 73%.
• Thrombin‐initiated fibrin clot kinetic assay and partial thromboplastin time best assessed HPB.

Summary

Background

Neonates undergoing cardiopulmonary bypass (CPB) are at risk of excessive bleeding. Blood is anticoagulated with heparin during CPB. Heparin activity is reversed with protamine at the end of CPB. Paradoxically, protamine also inhibits blood coagulation when it is dosed in excess of heparin.

Objectives

To evaluate heparin–protamine balance in neonates undergoing CPB by using research and clinical assays, and to determine its association with postoperative bleeding.

Patients/Methods

Neonates undergoing CPB in the first 30 days of life were studied. Blood samples were obtained during and after surgery. Heparin–protamine balance was assessed with calibrated automated thrombography, thrombin‐initiated fibrin clot kinetic assay (TFCK), activated partial thromboplastin time (APTT), anti‐FXa activity, and thromboelastometry. Excessive postoperative bleeding was determined by measurement of chest tube output or the development of cardiac tamponade.

Results and Conclusions

Of 44 neonates enrolled, 16 (36%) had excessive postoperative bleeding. The TFCK value was increased. By heparin in neonatal blood samples, but was only minimally altered by excess protamine. Therefore, it reliably measured heparin in samples containing a wide range of heparin and protamine concentrations. The APTT most closely correlated with TFCK results, whereas anti‐FXa and thromboelastometry assays were less correlative. The TFCK and APTT assay also consistently detected postoperative heparin rebound, providing an important continued role for these long‐established coagulation tests in the management of postoperative bleeding in neonates requiring cardiac surgical repair. None of the coagulation tests predicted the neonates who experienced postoperative bleeding, reflecting the multifactorial causes of bleeding in this population.

     

A comparison of INRs after local calibration of thromboplastin international sensitivity indexes.

There are approximately 300 reagent/instrument combinations for performing prothrombin times/international normalized ratios (PT/INR) in the United States. Manufacturers and laboratories continually struggle to ensure that the International Sensitivity Index (ISI) of their thromboplastin is accurate for assaying PT/INR. OBJECTIVE: This study reports the feasibility of a new method to locally calibrate ISI of thromboplastin using the mechanical STA automated coagulation analyzer (Diagnostica-Stago Inc.) and two photo-optic coagulation analyzers, the BCS (Dade-Behring) and CA-540 (Sysmex). DESIGN: Neoplastine CI+ (CI+) (Diagnostica-Stago Inc); Thromboplastin C+ (TC+); Thromborel S (TRS); and Innovin (I) (Dade-Behring) were used in this study. A mean normal PT (MNPT) was determined for each reagent/instrument combination using samples from 25 normal individuals. Manufacturer instrument specific ISI values were not available for the STA with TC+, TRS and I. The CA540 had no ISI value for CI+ and the BCS system had no manufacturer assigned ISI values for TC+ and I; generic photo-optic and mechanical ISI manufacturer values were used for these two systems. Local on-site calibration was performed using frozen plasma calibrators to determine ISI values for each thromboplastin. Post-calibration, 95 patient samples were assayed for each reagent/instrument system combination using the manufacturer ISI and the local calibrated ISI to determine the INR result. PATIENTS: Patients from whom samples were obtained included five with a lupus anticoagulant, 30 on heparin therapy, and 60 on coumadin therapy. RESULTS: Differences between manufacturer versus local calibrated ISI ranged from 0.9% to 18.9% for normal sample INRs and from 0.8% to 16.4% for patient sample INRs. The number (or proportion) of patient specimens with clinically significantly different INR values (>10.0% difference) ranged from zero for several reagent combinations to more than half (or >50.0%) of those tested for several other combinations. CONCLUSION: Our results indicated that by locally calibrating ISI values, each laboratory may eliminate variability and guesswork between different reagent/instrument systems for ISI values when performing PT/INR assays and potentially improve the clinical accuracy of their patients' PT/INR results.     

Venous thromboembolism in cancer patients receiving neoadjuvant chemotherapy: a systematic review and meta‐analysis

Essentials

• Cancer patients are at risk for venous thromboembolism (VTE).
• The risk of VTE in less advanced stage cancer on neoadjuvant chemotherapy is unclear.
• In over 7800 patients, we found a 7% pooled incidence of VTE during neoadjuvant therapy.
• Highest VTE rates were observed in patients with bladder and esophageal cancer.

Summary

Background

Venous thromboembolism (VTE) is a frequent complication in cancer patients receiving adjuvant treatment. The risk of VTE during neoadjuvant chemo‐radiotherapy remains unclear.

Objectives

This systematic review evaluated the incidence of VTE in patients with cancer receiving neoadjuvant treatment.

Methods

MEDLINE and EMBASE databases were searched from inception to October 2017. Search results were supplemented with screening of conference proceedings of the American Society of Clinical Oncology (2009–2016) and the International Society of Thrombosis and Haemostasis (2003–2016). Two review authors independently screened titles and abstracts, and extracted data onto standardized forms.

Results

Twenty‐eight cohort studies (7827 cancer patients, range 11 to 1398) were included. Twenty‐five had a retrospective design. Eighteen cohorts included patients with gastrointestinal cancer, representing over two‐thirds of the whole study population (n = 6002, 78%). In total, 508 of 7768 patients were diagnosed with at least one VTE during neoadjuvant treatment, for a pooled VTE incidence of 7% (95% CI, 5% to 10%) in the absence of substantial between‐study heterogeneity. Heterogeneity was not explained by site of cancer or study design characteristics. VTE presented as pulmonary embolism in 22% to 96% of cases (16 cohorts), and it was symptomatic in 22% to 100% of patients (11 cohorts). The highest VTE rates were observed in patients with bladder (10.6%) or esophageal (8.4%) cancer.

Conclusions

This review found a relatively high incidence of VTE in cancer patients receiving neoadjuvant therapy in the presence of some between‐study variation, which deserves further evaluation in prospective studies.

     

Phase 1, single‐dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant,in patients with severe hemophilia

Essentials

• Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII.
• A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia.
• MarzAA was safe and tolerated at intravenous doses up to 30 μg kg^?1
• Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX.

Summary

Background

Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia.

Objectives

To investigate the safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending intravenous bolus doses of MarzAA in non‐bleeding patients with congenital hemophilia A or B with or without inhibitors.

Methods

This international, phase 1, open‐label study (NCT01439971) enrolled males aged 18–64 years with severe hemophilia A or B, with or without FVIII or FIX inhibitors. Subjects were assigned to single‐dose MarzAA cohorts (0.5, 4.5, 9, 18 or 30 μg kg^?1). Blood sampling was performed predose and postdose, and subjects were monitored for 60 days postdose. Safety endpoints included adverse events, vital sign changes, electrocardiograms, laboratory abnormalities, and immunogenicity; secondary endpoints included evaluation of PK and PD.

Results

Overall, in 25 patients, MarzAA was well tolerated at all dose levels tested, and was not associated with dose‐limiting toxicity. No treatment‐emergent severe or serious adverse events occurred. MarzAA showed linear dose–response PK across the 4.5–30 μg kg^?1 dose range, with a terminal half‐life of ? 3.5 h. Dose‐dependent shortening of the activated partial thromboplastin time and prothrombin time, and evidence of an increase in peak thrombin as determined with a thrombin generation assay, were observed at all doses.

Conclusions

MarzAA was tolerated at doses up to 30 μg kg^?1. The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors.

     

International comparative field study evaluating the assay performance of AFSTYLA in plasma samples at clinical hemostasis laboratories

Essentials

• AFSTYLA exhibits ≈50% underestimation in activity when the one‐stage (OS) assay is utilized.
• A field study compared the performance of AFSTYLA with Advate in factor VIII activity assays.
• AFSTYLA activity can be monitored with both the chromogenic substrate and the OS assay.
• The consistent OS underestimation allows for a conversion factor to be applied to OS results.

Summary

Introduction

AFSTYLA (antihemophilic factor [recombinant] single chain) is a novel B‐domain truncated recombinant factor VIII (rFVIII). For AFSTYLA, an approximate 50% discrepancy was observed between results of the one‐stage (OS) and chromogenic substrate (ChS) FVIII activity assays. An investigation was undertaken to test whether there is a linear relationship between ChS and OS assay results that would allow reliable clinical interpretation of results independent of the assay method used.

Aims

To provide confidence in future clinical monitoring, this field study investigated the performance of AFSTYLA and a full‐length rFVIII (Advate^®) in FVIII activity assays routinely performed in clinical laboratories.

Methods

The comparison of AFSTYLA and Advate was performed in an international, multicenter and blinded field study of simulated post‐infusion samples. The study documented the extent of variability between methods and laboratories and characterized the relationship between the ChS and OS assays.

Results

Results from 23 laboratories demonstrate that intra and interlaboratory variability in OS assays were similar for both products. When comparing within the OS assay format, there was a similar and reagent‐correlated variability in response to different activators for both AFSTYLA and Advate. The OS underestimation was highly predictable and consistent across the complete range of FVIII plasma concentrations.

Conclusion

Post‐infusion plasma AFSTYLA levels can be monitored in patients by the OS and ChS assays. The consistent and predictable difference between the two assay formats provides clinicians with adequate guidance on how to interpret the results of the OS assay using a single conversion factor.     

Evaluation of the age‐dependent dosing recommendations for the administration of daily tinzaparin in children with thrombosis

Essentials

• The once‐daily dosing of tinzaparin provides an advantage over other low molecular weight heparins.
• The recommended age‐dependent doses of tinzaparin in children have not previously been validated.
• Once‐daily administration of tinzaparin is a safe and effective treatment of childhood thrombosis.
• Recommended doses are appropriate but monitoring may be required due to inter‐individual variation.

     

External validation of the PLASMIC score: a clinical prediction tool for thrombotic thrombocytopenic purpura diagnosis and treatment

Essentials

• Severe ADAMTS‐13 deficiency is key to thrombotic thrombocytopenic purpura (TTP) diagnosis.
• PLASMIC score predicts ADAMTS‐13 deficiency in suspected TTP with high discrimination.
• PLASMIC score is more generalizable with fewer missing data than alternative clinical scores.
• PLASMIC score identifies a subgroup of patients lacking significant response to plasma exchange.

Summary

Background

The PLASMIC score was recently published to distinguish patients with severe ADAMTS‐13 deficiency from those without for early identification of thrombotic thrombocytopenia purpura (TTP).

Objective

We performed an independent external validation of the PLASMIC score for clinical prediction of severe ADAMTS‐13 deficiency.

Patients/Methods

We studied an independent cohort of 112 consecutive hospitalized patients with suspected thrombotic microangiopathy and appropriate ADAMTS‐13 testing (including 21 patients with TTP diagnosis).

Results

The PLASMIC score model predicted severe ADAMTS‐13 deficiency with a c statistic of 0.94 (0.88–0.98). When dichotomized at high (score 6–7) vs. low‐intermediate risk (score 0–5), the model predicted severe ADAMTS‐13 deficiency with positive predictive value of 72%, negative predictive value of 98%, sensitivity of 90% and specificity of 92%. In the low‐intermediate risk group (score 0–5) there was no significant improvement in overall survival associated with plasma exchange.

Conclusions

The PLASMIC score model had excellent applicability, discrimination and calibration for predicting severe ADAMTS‐13 deficiency. The clinical algorithm allowed identification of a subgroup of patients who lacked a significant response to empiric treatment.     

Metabolomic analysis of 92 pulmonary embolism patients from a nested case–control study identifies metabolites associated with adverse clinical outcomes

Essentials

• Risk‐stratification often fails to predict clinical deterioration in pulmonary embolism (PE).
• First‐ever high‐throughput metabolomics analysis of risk‐stratified PE patients.
• Changes in circulating metabolites reflect a compromised energy metabolism in PE.
• Metabolites play a key role in the pathophysiology and risk stratification of PE.

Summary

Background

Patients with acute pulmonary embolism (PE) exhibit wide variation in clinical presentation and outcomes. Our understanding of the pathophysiologic mechanisms differentiating low‐risk and high‐risk PE is limited, so current risk‐stratification efforts often fail to predict clinical deterioration and are insufficient to guide management.

Objectives

To improve our understanding of the physiology differentiating low‐risk from high‐risk PE, we conducted the first‐ever high‐throughput metabolomics analysis (843 named metabolites) comparing PE patients across risk strata within a nested case–control study.

Patients/methods

We enrolled 92 patients diagnosed with acute PE and collected plasma within 24 h of PE diagnosis. We used linear regression and pathway analysis to identify metabolites and pathways associated with PE risk‐strata.

Results

When we compared 46 low‐risk with 46 intermediate/high‐risk PEs, 50 metabolites were significantly different after multiple testing correction. These metabolites were enriched in the following pathways: tricarboxylic acid (TCA) cycle, fatty acid metabolism (acyl carnitine) and purine metabolism, (hypo)xanthine/inosine containing. Additionally, energy, nucleotide and amino acid pathways were downregulated in intermediate/high‐risk PE patients. When we compared 28 intermediate‐risk with 18 high‐risk PE patients, 41 metabolites differed at a nominal P‐value level. These metabolites were enriched in fatty acid metabolism (acyl cholines), and hemoglobin and porphyrin metabolism.

Conclusion

Our results suggest that high‐throughput metabolomics can provide insight into the pathophysiology of PE. Specifically, changes in circulating metabolites reflect compromised energy metabolism in intermediate/high‐risk PE patients. These findings demonstrate the important role metabolites play in the pathophysiology of PE and highlight metabolomics as a potential tool for risk stratification of PE.

     

A first‐in‐human study of the safety,tolerability, pharmacokinetics and pharmacodynamics of PF‐06741086, an anti‐tissue factor pathway inhibitor mAb,in healthy volunteers

Essentials

• Tissue factor pathway inhibitor (TFPI) is an antagonist of FXa and the TF‐FVIIa complex.
• PF‐06741086 is an IgG₁ monoclonal antibody that targets the Kunitz‐2 domain of TFPI.
• Single doses of PF‐06741086 were evaluated in a phase 1 study in healthy volunteers.
• Data from this study support further investigation of PF‐06741086 in individuals with hemophilia.

Summary

Background

Tissue factor pathway inhibitor (TFPI) is a protease inhibitor of the tissue factor–activated factor VII complex and activated FX. PF‐06741086 is a mAb that targets TFPI to increase clotting activity.

Objectives

This study was a randomized, double‐blind, sponsor‐open, placebo‐controlled, single intravenous or subcutaneous dose escalation study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of PF‐06741086.

Patients/Methods

Volunteers who provided written informed consent were assigned to cohorts with escalating dose levels. Safety endpoints included treatment‐emergent adverse events (TEAEs), infusion/injection site reactions, vital signs, electrocardiogram, and coagulation and hematology laboratory parameters. Pharmacokinetic (PK) and pharmacodynamic (PD) endpoints included exposures of PF‐06741086 in plasma and measures of PF‐06741086 pharmacology, respectively.

Results

Forty‐one male volunteers were recruited overall. Thirty‐two were dosed with PF‐06741086 from 30 mg subcutaneously to 440 mg intravenously. All doses were safe and well tolerated. TEAEs were mild or moderate in severity, laboratory abnormalities were transient, there were no serious adverse events, there were no infusion/injection site reactions, and no dose escalation stopping criteria were met. Plasma exposures of PF‐06741086 increased greater than proportionally with dose under the same dosing route. Coagulation pharmacology was demonstrated via total TFPI, dilute prothrombin time, D‐dimer, prothrombin fragment 1 + 2 and thrombin generation assay parameters.

Conclusions

Single doses of PF‐06741086 at multiple dose levels were safe and well tolerated in a healthy adult male population. The safety, PK and PD data from this study support progression to a multiple‐dose study in hemophilic patients.

     

Mapping the rehabilitation interventions of a community stroke team to the extended International Classification of Functioning,Disability and Health Core Set for Stroke

Purpose: This study aim was to evaluate whether the Extended International Classification of Functioning, Disability and Health Core Set for Stroke captured the interventions of a community stroke rehabilitation team situated in a large city in New Zealand. It was proposed that the results would identify the contribution of each discipline, and the gaps and differences in service provision to Māori and non-Māori. Applying the Extended International Classification of Functioning, Disability and Health Core Set for Stroke in this way would also inform whether this core set should be adopted in New Zealand.

Method: Interventions were retrospectively extracted from 18 medical records and linked to the International Classification of Functioning, Disability and Health and the Extended International Classification of Functioning, Disability and Health Core Set for Stroke. The frequencies of linked interventions and the health discipline providing the intervention were calculated.

Results: Analysis revealed that 98.8% of interventions provided by the rehabilitation team could be linked to the Extended International Classification of Functioning, Disability and Health Core Set for Stroke, with more interventions for body function and structure than for activities and participation; no interventions for emotional concerns; and limited interventions for community, social and civic life. Results support previous recommendations for additions to the EICSS.

Conclusions: The results support the use of the Extended International Classification of Functioning, Disability and Health Core Set for Stroke in New Zealand and demonstrates its use as a quality assurance tool that can evaluate the scope and practice of a rehabilitation service.

• Implications for Rehabilitation

• The Extended International Classification of Functioning Disability and Health Core Set for Stroke appears to represent the stroke interventions of a community stroke rehabilitation team in New Zealand.

• As a result, researchers and clinicians may have increased confidence to use this core set in research and clinical practice.

• The Extended International Classification of Functioning Disability and Health Core Set for Stroke can be used as a quality assurance tool to establish whether a community stroke rehabilitation team is meeting the functional needs of its stroke population.

     

Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation,predicts the risk of venous thromboembolism in cancer patients

Essentials

• Neutrophil extracellular traps (NETs) might play a role in cancer‐related coagulopathy.
• We determined NET biomarkers and followed cancer patients for venous thromboembolism (VTE).
• We found a constant association with VTE for citrullinated histone H3.
• Biomarkers of NET formation could reflect a novel pathomechanism of cancer‐related VTE.

Summary

Background

Neutrophil extracellular traps (NETs) are decondensed chromatin fibers that might play a role in the prothrombotic state of cancer patients.

Objectives

To investigate whether the levels of citrullinated histone H3 (H3Cit), a biomarker for NET formation, cell‐free DNA (cfDNA) and nucleosomes predict venous thromboembolism (VTE) in cancer patients.

Patients/Methods

Nine‐hundred and forty‐six patients with newly diagnosed cancer or progression after remission were enrolled in this prospective observational cohort study. H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients were followed for 2 years. VTE occurred in 89 patients; the cumulative 3‐month, 6‐month, 12‐month and 24‐month incidence rates of VTE were 3.7%, 6.0%, 8.1%, and 10.0%, respectively.

Results

Patients with elevated H3Cit levels (> 75th percentile of its distribution, n = 236) experienced a higher cumulative incidence of VTE (2‐year risk of 14.5%) than patients with levels below this cut‐off (2‐year risk of 8.5%, n = 710). In a competing‐risk regression analysis, a 100 ng mL^?1 increase in H3Cit level was associated with a 13% relative increase in VTE risk (subdistribution hazard ratio [SHR] 1.13, 95% confidence interval [CI] 1.04–1.22). This association remained after adjustment for high VTE risk and very high VTE risk tumor sites, D‐dimer level, and soluble P‐selectin level (SHR 1.13, 95% CI 1.04–1.22). The association of elevated nucleosome and cfDNA levels with VTE risk was time‐dependent, with associations with a higher risk of VTE only during the first 3–6 months.

Conclusion

These data suggest that biomarkers of NET formation are associated with the occurrence of VTE in cancer patients, indicating a role of NETs in the pathogenesis of cancer‐associated thrombosis.

     

Polymorphism in dural arteriovenous fistula: matrix metalloproteinase‐2‐1306 C/T as a potential risk factor for sinus thrombosis

Essentials

• Sinus thrombosis may play a crucial role in development of dural arteriovenous fistula (DAVF).
• Little is known about the association between gene polymorphism and the development of DAVF.
• MMP‐2‐1306 C/T showed a higher prevalence rate in DAVF cases with sinus thrombosis.
• MMP‐2‐1306C/T polymorphism is likely a potential risk factor for sinus thrombosis in DAVF.

Summary

Background

Dural arteriovenous fistula (DAVF) is a rare but important cerebrovascular disorder in adults. Little is known about the molecular genetic pathogenesis underlying DAVF development.

Objectives

To investigate the associations of gene polymorphisms and DAVF.

Materials and Methods

By the use of real‐time PCR genotyping, seven single‐nucleotide polymorphisms (SNPs) of angiogenesis‐related genes were analyzed in 72 DAVF patients. Pertinent clinical and imaging data were subgrouped on the basis of location (cavernous sinus versus lateral sinus), lesions (single versus multiple), cerebral venous reflux (CVR) grading (Borden I versus Borden II/III), and sinus thrombosis (with versus without).

Results

We found that individuals carrying the polymorphic allele of matrix metalloproteinase (MMP)‐2‐1306 C/T (rs243865) had a significantly increased risk of sinus thrombosis in DAVF (odds ratio 6.2; 95% confidence interval 1.7–22.9). There was a weak difference in associations of tissue inhibitor of metalloproteinase (TIMP)‐2 (rs2277698) gene polymorphism and DAVF patients subgrouped by CVR grading.

Conclusions

These preliminary results indicate that MMP‐2‐1306 C/T, but not MMP‐9, TIMP‐1, TIMP‐2, and vascular endothelial growth factor A SNP variants, is a risk factor for the development of sinus thrombosis in DAVF patients.