Comprehensive Venous Outflow Predicts Functional Outcomes in Patients with Acute Ischemic Stroke Treated by Thrombectomy.

BACKGROUND AND PURPOSE: Cortical venous outflow has emerged as a robust measure of collateral blood flow in acute ischemic stroke. The addition of deep venous drainage to this assessment may provide valuable information to further guide the treatment of these patients. MATERIALS AND METHODS: We performed a multicenter retrospective cohort study of patients with acute ischemic stroke treated by thrombectomy between January 2013 and January 2021. The internal cerebral veins were scored on a scale of 0-2. This metric was combined with existing cortical vein opacification scores to create a comprehensive venous outflow score from 0 to 8 and stratify patients as having favorable-versus-unfavorable comprehensive venous outflow. Outcome analyses were primarily conducted using the Mann-Whitney U and χ2 tests. RESULTS: Six hundred seventy-eight patients met the inclusion criteria. Three hundred fifteen were stratified as having favorable comprehensive venous outflow (mean age, 73 years; range, 62-81 years; 170 men), and 363, as having unfavorable comprehensive venous outflow (mean age, 77 years; range, 67-85 years; 154 men). There were significantly higher rates of functional independence (mRS 0-2; 194/296 versus 37/352, 66% versus 11%, P < .001) and excellent reperfusion (TICI 2c/3; 166/313 versus 142/358, 53% versus 40%, P < .001) in patients with favorable comprehensive venous outflow. There was a significant increase in the association of mRS with the comprehensive venous outflow score compared with the cortical vein opacification score (-0.74 versus -0.67, P = .006). CONCLUSIONS: A favorable comprehensive venous profile is strongly associated with functional independence and excellent postthrombectomy reperfusion. Future studies should focus on patients with venous outflow status that is discrepant with the eventual outcome.

Detection of Early Ischemic Changes with Virtual Noncontrast Dual-Energy CT in Acute Ischemic Stroke: A Noninferiority Analysis.

BACKGROUND AND PURPOSE: Dual-energy virtual NCCT has the potential to replace conventional NCCT to detect early ischemic changes in acute ischemic stroke. In this study, we evaluated whether virtual NCCT is noninferior compared with standard linearly blended NCCT, a surrogate of conventional NCCT, regarding the detection of early ischemic changes with ASPECTS. MATERIALS AND METHODS: Adult patients who presented with suspected acute ischemic stroke and who underwent dual-energy NCCT and CTA and brain MR imaging within 48 hours were included. Standard linearly blended images were reconstructed to match a conventional NCCT. Virtual NCCT images were reconstructed from CTA. ASPECTS was evaluated on conventional NCCT, virtual NCCT, and DWI, which served as the reference standard. Agreement between CT assessments and the reference standard was evaluated with the Lin concordance correlation coefficient. Noninferiority was assessed with bootstrapped estimates of the differences in ASPECTS between conventional and virtual NCCT with 95% CIs. RESULTS: Of the 193 included patients, 100 patients (52%) had ischemia on DWI. Compared with the reference standard, the ASPECTS concordance correlation coefficient for conventional and virtual NCCT was 0.23 (95% CI, 0.15-0.32) and 0.44 (95% CI, 0.33-0.53), respectively. The difference in the concordance correlation coefficient between virtual and conventional NCCT was 0.20 (95% CI, 0.01-0.39) and did not cross the prespecified noninferiority margin of -0.10. CONCLUSIONS: Dual-energy virtual NCCT is noninferior compared with conventional NCCT for the detection of early ischemic changes with ASPECTS.

Prediction of Clinical Outcome in Patients with Large-Vessel Acute Ischemic Stroke: Performance of Machine Learning versus SPAN-100.

BACKGROUND AND PURPOSE: Traditional statistical models and pretreatment scoring systems have been used to predict the outcome for acute ischemic stroke patients (AIS). Our aim was to select the most relevant features in terms of outcome prediction on the basis of machine learning algorithms for patients with acute ischemic stroke and to compare the performance between multiple models and the Stroke Prognostication Using Age and National Institutes of Health Stroke Scale (SPAN-100) index model. MATERIALS AND METHODS: A retrospective multicenter cohort of 1431 patients with acute ischemic stroke was subdivided into recanalized and nonrecanalized patients. Extreme Gradient Boosting machine learning models were built to predict the mRS score at 90 days using clinical, imaging, combined, and best-performing features. Feature selection was performed using the relative weight and frequency of occurrence in the models. The model with the best performance was compared with the SPAN-100 index model using area under the receiver operating curve analysis. RESULTS: In 3 groups of patients, the baseline NIHSS was the most significant predictor of outcome among all the parameters, with relative weights of 0.36∼0.69; ischemic core volume on CTP ranked as the most important imaging biomarker with relative weights of 0.29∼0.47. The model with the best-performing features had a better performance than the other machine learning models. The area under the curve of the model with the best-performing features was higher than SPAN-100 model and reached statistical significance for the total (P < .05) and the nonrecanalized patients (P < .001). CONCLUSIONS: Machine learning-based feature selection can identify parameters with higher performance in outcome prediction. Machine learning models with the best-performing features, especially advanced CTP data, had superior performance of the recovery outcome prediction for patients with stroke at admission in comparison with SPAN-100.

Automated Cerebral Hemorrhage Detection Using RAPID.

BACKGROUND AND PURPOSE: Intracranial hemorrhage (ICH) is an important event that is diagnosed on head NCCT. Increased NCCT utilization in busy hospitals may limit timely identification of ICH. RAPID ICH is an automated hybrid 2D-3D convolutional neural network application designed to detect ICH that may allow for expedited ICH diagnosis. We determined the accuracy of RAPID ICH for ICH detection and ICH volumetric quantification on NCCT. MATERIALS AND METHODS: NCCT scans were evaluated for ICH by RAPID ICH. Consensus detection of ICH by 3 neuroradiology experts was used as the criterion standard for RAPID ICH comparison. ICH volume was also automatically determined by RAPID ICH in patients with intraparenchymal or intraventricular hemorrhage and compared with manually segmented ICH volumes by a single neuroradiology expert. ICH detection accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios by RAPID ICH were determined. RESULTS: We included 308 studies. RAPID ICH correctly identified 151/158 ICH cases and 143/150 ICH-negative cases, which resulted in high sensitivity (0.956, CI: 0.911-0.978), specificity (0.953, CI: 0.907-0.977), positive predictive value (0.956, CI: 0.911-0.978), and negative predictive value (0.953, CI: 0.907-0.977) for ICH detection. The positive likelihood ratio (20.479, CI 9.928-42.245) and negative likelihood ratio (0.046, CI 0.023-0.096) for ICH detection were similarly favorable. RAPID ICH volumetric quantification for intraparenchymal and intraventricular hemorrhages strongly correlated with expert manual segmentation (correlation coefficient r = 0.983); the median absolute error was 3 mL. CONCLUSIONS: RAPID ICH is highly accurate in the detection of ICH and in the volumetric quantification of intraparenchymal and intraventricular hemorrhages.

Hypoperfusion intensity ratio correlates with angiographic collaterals in acute ischaemic stroke with M1 occlusion.

BACKGROUND AND PURPOSE: Among patients with an acute ischaemic stroke secondary to large-vessel occlusion, the hypoperfusion intensity ratio (HIR) [time to maximum (TMax) > 10 volume/TMax > 6 volume] is a strong predictor of infarct growth. We studied the correlation between HIR and collaterals assessed with digital subtraction angiography (DSA) before thrombectomy. METHODS: Between January 2014 and March 2018, consecutive patients with an acute ischaemic stroke and an M1 middle cerebral artery (MCA) occlusion who underwent perfusion imaging and endovascular treatment at our center were screened. Ischaemic core (mL), HIR and perfusion mismatch (TMax > 6 s minus core volume) were assessed through magnetic resonance imaging or computed tomography perfusion. Collaterals were assessed on pre-intervention DSA using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) scale. Baseline clinical and perfusion characteristics were compared between patients with good (ASITN/SIR score 3-4) and those with poor (ASITN/SIR score 0-2) DSA collaterals. Correlation between HIR and ASITN/SIR scores was evaluated using Pearson's correlation. Receiver operating characteristic analysis was performed to determine the optimal HIR threshold for the prediction of good DSA collaterals. RESULTS: A total of 98 patients were included; 49% (48/98) had good DSA collaterals and these patients had significantly smaller hypoperfusion volumes (TMax > 6 s, 89 vs. 125 mL; P = 0.007) and perfusion mismatch volumes (72 vs. 89 mL; P = 0.016). HIR was significantly correlated with DSA collaterals (-0.327; 95% confidence interval, -0.494 to -0.138; P = 0.01). An HIR cut-off of <0.4 best predicted good DSA collaterals with an odds ratio of 4.3 (95% confidence interval, 1.8-10.1) (sensitivity, 0.792; specificity, 0.560; area under curve, 0.708). CONCLUSION: The HIR is a robust indicator of angiographic collaterals and might be used as a surrogate of collateral assessment in patients undergoing magnetic resonance imaging. HIR <0.4 best predicted good DSA collaterals.

Patient Outcomes and Cerebral Infarction after Ruptured Anterior Communicating Artery Aneurysm Treatment.

BACKGROUND AND PURPOSE: Anterior communicating artery aneurysm rupture and treatment is associated with high rates of dependency, which are more severe after clipping compared with coiling. To determine whether ischemic injury might account for these differences, we characterized cerebral infarction burden, infarction patterns, and patient outcomes after surgical or endovascular treatment of ruptured anterior communicating artery aneurysms. MATERIALS AND METHODS: We performed a retrospective cohort study of consecutive patients with ruptured anterior communicating artery aneurysms. Patient data and neuroimaging studies were reviewed. A propensity score for outcome measures was calculated to account for the nonrandom assignment to treatment. Primary outcome was the frequency of frontal lobe and striatum ischemic injury. Secondary outcomes were patient mortality and clinical outcome at discharge and at 3 months. RESULTS: Coiled patients were older (median, 55 versus 50 years; P = .03), presented with a worse clinical status (60% with Hunt and Hess Score >2 versus 34% in clipped patients; P = .02), had a higher modified Fisher grade (P = .01), and were more likely to present with intraventricular hemorrhage (78% versus 56%; P = .03). Ischemic frontal lobe infarction (OR, 2.9; 95% CI, 1.1-8.4; P = .03) and recurrent artery of Heubner infarction (OR, 20.9; 95% CI, 3.5-403.7; P < .001) were more common in clipped patients. Clipped patients were more likely to be functionally dependent at discharge (OR, 3.2; P = .05) compared with coiled patients. Mortality and clinical outcome at 3 months were similar between coiled and clipped patients. CONCLUSIONS: Frontal lobe and recurrent artery of Heubner infarctions are more common after surgical clipping of ruptured anterior communicating artery aneurysms, and are associated with poorer clinical outcomes at discharge.

The association of anti-platelet factor 4/heparin antibodies with early and delayed thromboembolism after cardiac surgery.

Essentials We evaluated antibody status, thromboembolism and survival after cardiac surgery. Positive antibody tests are common - over 50% are seropositive at 30 days. Seropositivity did not increase thromboembolism or impair survival after cardiac surgery. Results show heparin induced thrombocytopenia antibody screening after surgery is not warranted. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is a prothrombotic response to heparin therapy with platelet-activating, anti-platelet factor 4 (PF4)/heparin antibodies leading to thrombocytopenia associated with thromboembolism. Objective We tested the hypothesis that anti-PF4/heparin antibodies are associated with thromboembolism after cardiac surgery. Methods This multicenter, prospective cohort study collected laboratory and clinical data up to 30 days after surgery and longer-term clinical follow-up data. The primary outcome variable combined new arterial or venous thromboembolic complications (TECs) with all-cause death until 90 days after surgery. Laboratory analyses included platelet counts and anti-PF4/heparin antibody titers (GTI ELISA), with a confirmatory excess heparin step and serotonin release assay. Chi-square testing was used to test the relationship between our outcome and HIT antibody seropositivity. Results Initially, 1021 patients were enrolled between August 2006 and May 2009, and follow-up was completed in December 2014. Seropositivity defined by OD > 0.4 was common, being almost 20% preoperatively, > 30% by discharge, and > 60% by day 30. Death (1.7% within 30 days) or TECs (69 in total) were more likely if the partient was seronegative (OD < 0.4), but positivity defined by OD > 1.0 or including an excess heparin confirmatory step resulted in equal incidence of death or TECs, whether the patient was seronegative or seropositive. Incorporating the serotonin release assay for platelet-activating antibodies did not alter these findings. Conclusions Seropositivity for anti-PF4/heparin antibodies does not increase the risk of death or thromboembolism after cardiac surgery. Screening is not indicated, and seropositivity should only be interpreted in the context of clinical evidence for HIT. TRIAL REGISTRATION: Duke IRB Protocol #00010736.

Do incident and recurrent venous thromboembolism risks truly differ between heterozygous and homozygous Factor V Leiden carriers? A retrospective cohort study.

INTRODUCTION: While Factor V Leiden (F5 rs6025 A allele) is a known venous thromboembolism (VTE) risk factor, VTE risk among heterozygous vs. homozygous carriers is uncertain. MATERIALS AND METHODS: In a retrospective cohort study of Mayo Clinic patients referred for genotyping between 1996 and 2013, we tested Factor V Leiden genotype as a risk factor for incident and recurrent VTE. RESULTS: Among heterozygous (n=268) and homozygous (n=111) carriers, the prevalence of VTE was 54% and 68%, respectively (p=0.016). While mean patient age at first VTE event (43.9 vs. 42.9years; p=0.70) did not differ significantly, median VTE-free survival was modestly shorter for homozygous carriers (56.8 vs 59.5 years; p=0.04). Sixty-nine (48%) and 31 (42%) heterozygous and homozygous carriers had ≥1 VTE recurrence (p=0.42). In a multivariable model, idiopathic incident VTE and a second thrombophilia were associated with increased and anticoagulation duration >6months with reduced hazards of VTE recurrence; Factor V Leiden genotype was not an independent predictor of recurrence. CONCLUSIONS: Aside from a higher VTE prevalence and modestly reduced VTE-free survival, VTE penetrance and phenotype severity did not differ significantly among homozygous vs. heterozygous carriers, suggesting that VTE prophylaxis and management should not differ by Factor V Leiden genotype.

Cerebral Angiography for Evaluation of Patients with CT Angiogram-Negative Subarachnoid Hemorrhage: An 11-Year Experience.

BACKGROUND AND PURPOSE: CT angiography is increasingly used to evaluate patients with nontraumatic subarachnoid hemorrhage given its high sensitivity for aneurysms. We investigated the yield of digital subtraction angiography among patients with SAH or intraventricular hemorrhage and a negative CTA. MATERIALS AND METHODS: An 11-year, single-center retrospective review of all consecutive patients with CTA-negative SAH was performed. Noncontrast head CT, CTA, DSA, and MR imaging studies were reviewed by 2 experienced interventional neuroradiologists and 1 neuroradiologist. RESULTS: Two hundred thirty patients (mean age, 54 years; 51% male) with CTA-negative SAH were identified. The pattern of SAH was diffuse (40%), perimesencephalic (31%), sulcal (31%), isolated IVH (6%), or identified by xanthochromia (7%). Initial DSA yield was 13%, including vasculitis/vasculopathy (7%), aneurysm (5%), arteriovenous malformation (0.5%), and dural arteriovenous fistula (0.5%). An additional 6 aneurysms/pseudoaneurysms (4%) were identified by follow-up DSA, and a single cavernous malformation (0.4%) was identified by MRI. No cause of hemorrhage was identified in any patient presenting with isolated intraventricular hemorrhage or xanthochromia. Diffuse SAH was due to aneurysm rupture (17%); perimesencephalic SAH was due to aneurysm rupture (3%) or vasculitis/vasculopathy (1.5%); and sulcal SAH was due to vasculitis/vasculopathy (32%), arteriovenous malformation (3%), or dural arteriovenous fistula (3%). CONCLUSIONS: DSA identifies vascular pathology in 13% of patients with CTA-negative SAH. Aneurysms or pseudoaneurysms are identified in an additional 4% of patients by repeat DSA following an initially negative DSA. All patients with CT-negative SAH should be considered for DSA. The pattern of SAH may suggest the cause of hemorrhage, and aneurysms should specifically be sought with diffuse or perimesencephalic SAH.

Incidence of venous thromboembolism after elective knee arthroscopic surgery: a historical cohort study.

BACKGROUND: The incidence of symptomatic venous thromboembolism (VTE) after knee arthroscopy is uncertain. OBJECTIVES: To estimate the incidence of symptomatic VTE after arthroscopic knee surgery. METHODS: In a population-based historical cohort study, all Olmsted County, MN, USA, residents undergoing a first arthroscopic knee surgery during the 18-year period of 1988-2005 were followed for incident deep venous thrombosis or pulmonary embolism. The cumulative incidence of VTE after knee arthroscopy was determined using the Kaplan-Meier product limit estimator. Patient age at surgery, sex, calendar year of surgery, body mass index, anesthesia characteristics, and hospitalization were tested as potential predictors of VTE using Cox proportional hazards modeling, both univariately and adjusted for age and sex. RESULTS: Among 4833 Olmsted County residents with knee arthroscopy, 18 developed postoperative VTE, all within the first 6 weeks after surgery. The cumulative incidence rates of symptomatic VTE at 7, 14, and 35 days were 0.2%, 0.3%, and 0.4%, respectively. The hazard for postoperative VTE was significantly increased for older patient age (hazard ratio = 1.34 for each 10-year increase in patient age; P = 0.03) and hospitalization either before or after knee arthroscopy (hazard ratio = 14.1; P < 0.001). CONCLUSIONS: The incidence of symptomatic VTE after arthroscopic knee surgery is very low. Older age and hospitalization are associated with increased risk. Routine prophylaxis to prevent symptomatic VTE is likely not needed in this patient population.

A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q.

OBJECTIVES: To identify venous thromboembolism (VTE) disease-susceptibility genes. PATIENTS AND METHODS: We performed in silico genome wide association scan (GWAS) analyses using genotype data imputed to approximately 2.5 million single-nucleotide polymorphisms (SNPs) from adults with objectively-diagnosed VTE (n=1503), and controls frequency matched on age and gender (n=1459; discovery population). Single-nucleotide polymorphisms exceeding genome-wide significance were replicated in a separate population (VTE cases, n=1407; controls, n=1418). Genes associated with VTE were re-sequenced. RESULTS: Seven SNPs exceeded genome-wide significance (P<5×10(-8)): four on chromosome 1q24.2 (F5 rs6025 [factor V Leiden], BLZF1 rs7538157, NME7 rs16861990 and SLC19A2 rs2038024) and three on chromosome 9q34.2 (ABO rs2519093 [ABO intron 1], rs495828, rs8176719 [ABO blood type O allele]). The replication study confirmed a significant association of F5, NME7 and ABO with VTE. However, F5 was the main signal on 1q24.2 as only ABO SNPs remained significantly associated with VTE after adjusting for F5 rs6025. This 1q24.2 region was shown to be inherited as a haplotype block. ABO re-sequencing identified 15 novel single nucleotide variations (SNV) in ABO intron 6 and the ABO 3' UTR that were strongly associated with VTE (P<10(-4)) and belonged to three distinct linkage disequilibrium (LD) blocks; none were in LD with ABO rs8176719 or rs2519093. Our sample size provided 80% power to detect odds ratios (ORs)=2.0 and 1.51 for minor allele frequencies=0.05 and 0.5, respectively (α=1×10(-8); 1% VTE prevalence). CONCLUSIONS: Apart from F5 rs6025, ABO rs8176719, rs2519093 and F2 rs1799963, additional common and high VTE-risk SNPs among whites are unlikely.

Cancer effect on periprocedural thromboembolism and bleeding in anticoagulated patients.

BACKGROUND: Patients with active cancer are often on chronic anticoagulation and frequently require interruption of this treatment for invasive procedures. The impact of cancer on periprocedural thromboembolism (TE) and major bleeding is not known. PATIENTS AND METHODS: Two thousand one hundred and eighty-two consecutive patients referred for periprocedural anticoagulation (2484 procedures) using a standardized protocol were followed forward in time to estimate the 3-month incidence of TE, major bleeding and survival stratified by anticoagulation indication. For each indication, we tested active cancer and bridging heparin therapy as potential predictors of TE and major bleeding. RESULTS: Compared with patients without cancer, active cancer patients (n=493) had more venous thromboembolism (VTE) complications (1.2% versus 0.2%; P=0.001), major bleeding (3.4% versus 1.7%; P=0.02) and reduced survival (95% versus 99%; P<0.001). Among active cancer patients, only those chronically anticoagulated for VTE had higher rates of periprocedural VTE (2% versus 0.16%; P=0.002) and major bleeding (3.7% versus 0.6%; P<0.001). Bridging with heparin increased the rate of major bleeding in cancer patients (5% versus 1%; P=0.03) without impacting the VTE rate (0.7% versus 1.4%, P=0.50). CONCLUSIONS: Cancer patients anticoagulated for VTE experience higher rates of periprocedural VTE and major bleeding. Periprocedural anticoagulation for these patients requires particular attention to reduce these complications.

Predictors of major bleeding in peri-procedural anticoagulation management.

BACKGROUND: Appropriate periprocedural management for chronically anticoagulated patients requires assessment of patient-specific thrombosis and bleeding risks. However, predictors of post-procedure bleeding are unknown. OBJECTIVES: To determine the 3-month cumulative incidence and independent predictors of peri-procedural bleeding in chronically anticoagulated patients requiring temporary warfarin interruption for an invasive procedure. METHODS: In a protocol driven, cohort study design, all patients referred to the Mayo Clinic Thrombophilia Center for peri-procedural anticoagulation management (1997-2007; n = 2182), were followed forward in time to determine the 3-month cumulative incidence of peri-procedural bleeding (Kaplan-Meier product limit) and potential predictors of bleeding (Cox proportional hazards). Decisions to 'bridge' with low-molecular-weight heparin were based on estimated thromboembolism and bleeding risk. RESULTS: Indications for chronic anticoagulation included venous thromboembolism (38%), atrial fibrillation (30%) and mechanical heart valves (27%). Of these, 1496 (69%) patients received bridging therapy. The 3-month cumulative incidence rates of major and overall bleeding were 2.1% and 5.1%, respectively. Major bleeding occurred more frequently in patients receiving bridging therapy (3% vs. 1%; P = 0.017). Independent predictors (hazard ratio; 95% confidence interval) of major bleeding included mitral mechanical heart valve (2.2; 1.1-4.3), active cancer (1.8; 1.0-3.1), prior bleeding history (2.6; 1.5-4.5) and re-initiation of heparin therapy within 24 h after the procedure (1.9; 1.1-3.4). CONCLUSION: Factors predisposing to peri-procedural bleeding are primarily patient-specific. Premature heparin re-initiation is an avoidable provider-specific variable to consider.

Validation of an automated latex particle-enhanced immunoturbidimetric von Willebrand factor activity assay.

BACKGROUND: Laboratory diagnosis of von Willebrand disease (VWD) requires accurate measurement of plasma von Willebrand factor (VWF) activity. OBJECTIVES: To evaluate laboratory characteristics, diagnostic accuracy and testing utilities of an automated latex particle-enhanced immunoturbidimetric VWF assay (VWF:Lx) based on a monoclonal antibody recognizing the VWF-platelet glycoprotein (GP) Ib binding domain. METHODS: Laboratory characteristics including lower detection limit, linearity, precision, sample stability, and method comparison between VWF:Lx and VWF ristocetin cofactor activity by platelet aggregometry (VWF:RCo) were examined. To assess VWF:Lx diagnostic accuracy, 492 patient plasma samples, including 40 previously characterized VWD patient samples, were tested for VWF antigen (VWF:Ag) and VWF:RCo by either aggregometry or flow cytometry, and VWF:Lx with supplemental VWF multimer analysis when indicated. Based on results of VWF:Ag, VWF:RCo and VWF multimer analysis, and available clinical information, samples were categorized as: normal; VWD types 1, 2A/B, 2M, or severe 1 vs. 2M; or acquired VWF abnormalities (AVWA) due to subtle loss of highest molecular weight multimers. RESULTS: VWF:Lx had excellent laboratory characteristics and linear correlation with VWF:RCo (R(2) = 0.93). VWF:Lx accurately classified virtually all normal and VWD patient samples. Compared with VWF:RCo, VWF:Lx had superior sensitivity and specificity for distinguishing severe type 1 vs. 2M VWD and identifying AVWA. A proposed screening panel comprising VWF:Ag and VWF:Lx had 100% and 83% sensitivity for detecting VWD and AVWA, respectively. CONCLUSIONS: VWF:Lx has excellent laboratory characteristics and diagnostic accuracy compared with VWF:RCo, and can be used as part of an initial VWD screening panel and as a supplementary test.

Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is highly heritable (estimated heritability [h(2)]=0.62) and likely to be a result of multigenic action. OBJECTIVE: To systematically test variation within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways for an independent association with VTE. METHODS: Non-Hispanic adults of European ancestry with objectively-diagnosed VTE, and age- and sex- matched controls, were genotyped for 13 031 single nucleotide polymorphisms (SNPs) within 764 genes. Analyses (n=12296 SNPs) were performed with plink using an additive genetic model and adjusted for age, sex, state of residence, and myocardial infarction or stroke. RESULTS: Among 2927 individuals, one or more SNPs within ABO, F2, F5, F11, KLKB1, SELP and SCUBE1 were significantly associated with VTE, including factor (F) V Leiden, prothrombin G20210A, ABO non-O blood type, and a novel association with ABO rs2519093 (OR=1.68, P-value=8.08×10(-16) ) that was independent of blood type. In stratified analyses, SNPs in the following genes were significantly associated with VTE: F5 and ABO among both genders and LY86 among women; F2, ABO and KLKB1 among FV Leiden non-carriers; F5, F11, KLKB1 and GFRA1 in those with ABO non-O blood type; and ABO, F5, F11, KLKB1, SCUBE1 and SELP among prothrombin G20210A non-carriers. The ABO rs2519093 population-attributable risk (PAR) exceeded that of FV Leiden and prothrombin G20210A, and the joint PAR of FV Leiden, prothrombin G20210A, ABO non-O and ABO rs2519093 was 0.40. CONCLUSIONS: Anticoagulant, procoagulant, fibrinolytic and innate immunity pathway genetic variation accounts for a large proportion of VTE among non-Hispanic adults of European ancestry.

The spectrum of haemostatic characteristics of women with unexplained menorrhagia.

While an estimated 13% of women with unexplained menorrhagia have von Willebrand disease (VWD), the frequency of other potential bleeding disorders has been uncertain. This study describes the relatively wide range of laboratory characteristics of women with unexplained menorrhagia and presents issues affecting diagnosis in this population. Women with pictorial blood assessment chart (PBAC) score > 100 were identified at six U.S. sites and asked to remain drug free for 10 days prior to testing. Blood was collected on one of the first four menstrual cycle days and tested at a central laboratory for procoagulant factors, VWD and fibrinolytic factors. Platelet function testing by PFA-100® (PFA) and platelet aggregation with ATP release (PAGG/ATPR) were performed locally using standardized methods. Among 232 subjects, a laboratory abnormality was found in 170 (73.3%), including 124 of 182 White (68.1%) and 34 of 37 Black (91.9%) subjects; 6.0% had VWD, 56.0% had abnormal PAGG/ATPR, 4.7% had a non-VWD coagulation defect (NVCD) and 6.5% had an abnormal PFA only. AGG/ATPR was reduced in 58.9% of subjects, with multiple agonists in 28.6%, a single agonist in 6.1% and ristocetin alone in 24.2%. Frequencies of PAGG/ATPR defects varied by study site and race; frequencies of VWD and NVCD were similar. Laboratory abnormalities of haemostasis, especially platelet function defects, were common among women with unexplained menorrhagia across multiple U.S. sites. To what degree these abnormalities are clinically significant requires further study.

Procoagulant activity, but not number, of microparticles increases with age and in individuals after a single venous thromboembolism.

The Calibrated Automated Thrombogram (CAT), a plate-based assay that measures thrombin generation and inhibition in plasma samples, is modified to measure the procoagulant activity of phospholipid associated with plasma microparticles (MP). The assay uses a tissue factor trigger without addition of 4 µM exogenous phospholipid (PL) used in the standard CAT. Calibrated with 4:1 posphatidylcholine- phosphatidylserine (PCPS) liposomes, the assay defines a median of 40 nM procoagulant phospholipid (PPL) equivalents in plasma containing MPs from 50 normal donors, with a range from 20 - 200 nM. Like the standard CAT, the modified assay detected no difference in plasma from 36 individuals with a history of a single episode of venous thromboembolism. However the male cases had double the PPL activity, as measured by rate of thrombin generation, of females; and there was a significant correlation among cases of increased thrombin generation with age. In contrast, there were no gender disparities or age correlations among control plasmas. The findings suggest that procoagulant activity of plasma microparticles, facilitated by a simplified, one-stage plate-based assay, offer a promising avenue of investigation of mechanisms and management of venous thromboembolic disorders.