Investigation of factors that may affect the foveal avascular zone: An optical coherence tomography angiography study.

SIGNIFICANCE: An understanding of factors that affect the foveal avascular zone (FAZ) in healthy eyes may aid in the early identification of patients at risk of retinal pathology, thereby allowing better management and preventive measures to be implemented. PURPOSE: The size and shape of the FAZ can change due to retinal diseases associated with oxidative stress, including diabetic retinopathy, glaucoma, and macular degeneration. This study aimed to assess the relationship, if any, between factors that may affect the superficial FAZ (i.e., vessel density, vessel perfusion, overweight/obesity) and possible links with macular pigment optical density in young, healthy participants. METHODS: One hundred thirty-nine participants aged 18 to 35 years were recruited to this cross-sectional study. The superficial FAZ area, foveal vascularity, and central macular thickness (CMT) were assessed using the Cirrus 5000. Health parameters, body mass index, trunk fat %, and macular pigment were analyzed to determine possible associations with the superficial FAZ. RESULTS: Mean FAZ area was 0.23 ± 0.08 mm2. Females had a significantly larger mean FAZ area than males (p=0.002). The FAZ area was positively correlated with body mass index (Pearson's r = 0.189, p=0.026). Significant correlates of the FAZ area in the multivariate model included vessel perfusion (central), CMT, and trunk fat %, collectively explaining 65.1% of the overall variability. CONCLUSIONS: Study findings suggest that reduced vessel perfusion, thinner CMT, and higher trunk fat % are plausible predictors of a larger FAZ area in healthy Caucasian adults. Low macular pigment optical density was, however, not associated with increased FAZ size in young healthy eyes. Noninvasive optical coherence tomography angiography testing, in association with these predictors, may aid in the early detection and monitoring of retinal diseases associated with oxidative stress.

Heterogeneity in the half-life of factor VIII concentrate in patients with hemophilia A is due to variability in the clearance of endogenous von Willebrand factor.

BACKGROUND: Previous studies have reported marked interindividual variation in factor VIII (FVIII) clearance in patients with hemophilia (PWH) and proposed a number of factors that influence this heterogeneity. OBJECTIVES: To investigate the importance of the clearance rates of endogenous von Willebrand factor (VWF) compared with those of other FVIII half-life modifiers in adult PWH. METHODS: The half-life of recombinant FVIII was determined in a cohort of 61 adult PWH. A range of reported modifiers of FVIII clearance was assessed (including plasma VWF:antigen and VWF propeptide levels; VWF-FVIII binding capacity; ABO blood group; and nonneutralizing anti-FVIII antibodies). The FVIII-binding region of the VWF gene was sequenced. Finally, the effects of variation in FVIII half-life on clinical phenotype were investigated. RESULTS: We demonstrated that heterogeneity in the clearance of endogenous plasma VWF is a key determinant of variable FVIII half-life in PWH. Both ABO blood group and age significantly impact FVIII clearance. The effect of ABO blood group on FVIII half-life in PWH is modulated entirely through its effect on the clearance rates of endogenous VWF. In contrast, the age-related effect on FVIII clearance is, at least in part, VWF independent. In contrast to previous studies, no major effects of variation in VWF-FVIII binding affinity on FVIII clearance were observed. Although high-titer immunoglobulin G antibodies (≥1:80) were observed in 26% of PWH, these did not impact FVIII half-life. Importantly, the annual FVIII usage (IU/kg/y) was significantly (p = .0035) increased in patients with an FVIII half-life of <12 hours. CONCLUSION: Our data demonstrate that heterogeneity in the half-life of FVIII concentrates in patients with hemophilia A is primarily attributable to variability in the clearance of endogenous VWF.

Normative data on the foveal avascular zone in a young healthy Irish population using optical coherence tomography angiography.

PURPOSE: To establish normative data on the size, shape and vascular profile of the foveal avascular zone (FAZ) in a young, healthy, Irish population, using the Cirrus 5000 HD-OCT. Certain diseases may alter FAZ appearance. Normative databases provide normal baseline values for comparison, thus improving diagnostic ability. METHODS: One hundred and fifty-four subjects aged 18-35 years old were recruited. Superficial FAZ area, diameter, circularity, ganglion cell layer, central macular thickness (CMT), vascular perfusion and density were measured using the Cirrus 5000. Axial length was measured with the IOL Master and blood pressure was measured using the Omron sphygmomanometer. RESULTS: Mean FAZ area was 0.22 ± 0.07 mm2, mean CMT was 263.08 ± 18.73µm. Both were larger in females than males (p = 0.022, p = 0.000). Mean vessel density and perfusion central were 14.11 ± 2.77 mm/mm2 and 24.70 ± 4.96% respectively. Both were lower in females (p = 0.010, p = 0.019). Vessel density and perfusion inner correlated positively with minimum ganglion cell layer plus inner plexiform layer (GCL + IPL) thickness (p = 0.001, p = 0.019). CMT correlated positively with vessel density and perfusion central (p = 0.000 for both) and negatively with FAZ area (p = 0.000). CONCLUSIONS: This study provides normative data for FAZ appearance and vascularity for the first time in a young, healthy, Irish population, using the Cirrus 5000 HD-OCT. Establishing machine and population specific normative data, particularly in relation to vessel density and perfusion is paramount to the early identification of ocular disease using Optical Coherence Tomography Angiography.

Plasma Thrombin Generation and Sensitivity to Activated Protein C Among Patients With Myeloma and Monoclonal Gammopathy of Undetermined Significance.

The etiology of the prothrombotic state in myeloma has yet to be definitively characterized. Similarly, while recent evidence suggests that patients with monoclonal gammopathy of undetermined significance (MGUS) may also be at increased risk of thrombosis, the magnitude and the etiology of this risk have also yet to be defined. The present study aims to characterize patterns of plasma thrombin generation and sensitivity to the anticoagulant activity of activated protein C (APC) at the time of initial diagnosis of myeloma and in response to therapy in comparison to that observed among patients with MGUS and matched, healthy volunteers. Patients presenting with newly diagnosed/newly relapsed myeloma (n = 8), MGUS (n = 8), and matched healthy volunteers (n = 8) were recruited. Plasma thrombin generation was determined by calibrated automated thrombography. Peak thrombin generation was significantly higher in patients with myeloma (383.4 ± 33.4 nmol/L) and MGUS (353.4 ± 16.5 nmol/L) compared to healthy volunteers (276.7 ± 20.8 nmol/L; P < .05). In the presence of APC, endogenous thrombin potential was significantly lower in control plasma (228.6 ± 44.5 nmol/L × min) than in either myeloma (866.2 ± 241.3 nmol/L × min, P = .01) or MGUS plasma (627 ± 91.5 nmol/L × min, P = .003). Within the myeloma cohort, peak thrombin generation was significantly higher at diagnosis (353.2 ± 15.9 nmol/L) than following completion of the third cycle of therapy (282.1 ± 15.2 nmol/L; P < .005). Moreover, sensitivity to APC increased progressively with each cycle of chemotherapy. Further study of the etiology and evolving patterns of hypercoagulability among patients with these conditions is warranted and may have future implications for thromboprophylaxis strategies.

Differing coagulation profiles of patients with monoclonal gammopathy of undetermined significance and multiple myeloma.

The link between myeloma and thrombosis is well established. Monoclonal gammopathy of undetermined significance (MGUS) has also been associated with an increased risk of thrombosis. It was recently demonstrated that patients with myeloma display changes in thromboelastometry that may indicate a prothrombotic state. There is little data with regard to changes in thromboelastography in patients with myeloma or MGUS. The aim of this study was to investigate the differing coagulation profiles of patients of patients with myeloma and MGUS by means of conventional coagulation tests and thromboelastography. Blood was taken by direct venepuncture from patients with myeloma, MGUS and normal controls. Routine coagulation tests were performed in an accredited hospital laboratory. Thromboelastography (TEG(®)) was performed as per the manufacturer's protocol. Eight patients were recruited in each group. Patients with myeloma had a significantly lower mean haemoglobin level than patients with MGUS or normal controls (p < 0.001). Patients with myeloma had a significantly more prolonged mean prothrombin time than normal controls (p = 0.018) but not patients with MGUS. Patients with myeloma had significantly higher median D-dimer levels than normal controls (p = 0.025), as did patients with MGUS (p = 0.017). Patients with myeloma had a significantly higher mean factor VIII level than normal controls (p = 0.009) and there was a non-significant trend towards patients with MGUS having higher factor VIII levels than normal controls (p = 0.059). There was no significant difference in thromboelastographic parameters between the three groups. Patients with MGUS appear to have a distinct coagulation profile which is intermediate between patients with myeloma and normal controls.

Associations between health literacy and beliefs about medicines in an Irish obstetric population.

The authors wanted to determine the prevalence of limited health literacy, and the relation between health literacy and beliefs about medicines, in an obstetric population. A survey was administered in Cork University Maternity Hospital, Cork, Ireland. The Rapid Estimate of Adult Literacy in Medicine and the general section of the Beliefs About Medicines Questionnaire were used. Of 404 women, 15.3% (n=62) displayed limited health literacy. Age and health literacy were significantly associated with one another, as were health literacy and level at which participants completed formal education. In the general harm domain, level of education and health literacy were associated with stronger beliefs: M=11.85, SD=2.81 vs. M=9.75, SD=2.11; F(3)=13.69, p<.001. In the general overuse domain, those with limited literacy scored higher compared with those with adequate health literacy: M=12.48, SD=2.73 versus M=11.51, SD=2.63 (p=.01). These associations remained despite controlling for age (and education) in multivariable analyses. More than 1 in 7 had limited health literacy; these women may benefit from educational initiatives. Limited health literacy is associated with a more negative perception of medicines in this cohort.

Weight-adjusted LMWH prophylaxis provides more effective thrombin inhibition in morbidly obese pregnant women.

INTRODUCTION: Low molecular weight heparin (LMWH) prophylaxis has been recommended for morbidly obese pregnant women (>40kg/m(2)). There is very little data on the anticoagulant effects of LMWH in this group. We investigated two different dosing regimens; fixed dose and weight-adjusted dose on the anticoagulant effects of the LMWH tinzaparin used for thromboprophylaxis in obese pregnant women. MATERIALS AND METHODS: Twenty morbidly obese pregnant women were started on a fixed dose of tinzaparin (4,500 iu/day) at 32weeks gestation and then changed to a weight-adjusted dose (75iu/kg/day) for the remainder of their pregnancy. Four-hour post LMWH, venous bloods were taken after each initial dose and repeated every two weeks until delivery. Twenty normal weight women who did not receive LMWH at the same gestation were used as controls. RESULTS: Prior to LMWH prophylaxis, tissue factor pathway inhibitor (TFPI) levels in the obese group at 32weeks were significantly lower (p<0.001) and endogenous thrombin potential (ETP) and peak thrombin levels in obese group were significantly higher, compared with controls (p<0.0001; p<0.001). There was no significant difference between ETP levels before and after fixed LMWH. However, ETP levels were significantly lower post weight-adjusted dose compared with post fixed dose. There was a significant effect of LMWH on TFPI levels, (p<0.0001). ETP correlated positively with total body weight prior to LMWH (r=0.631) (p<0.05) and at fixed dose (r=0.578) (p<0.05). CONCLUSION: Morbidly obese pregnant women have increased thrombin generation and reduced natural anticoagulant in third trimester. This prothrombotic state was more effectively attenuated by weight-adjusted than fixed LMWH doses.

Venous thromboembolism in patients with myeloma: incidence and risk factors in a "real-world" population.

Myeloma has a well-described association with venous thromboembolism (VTE). There are few dedicated studies investigating the incidence and risk factors. Many assessment scores have been suggested to estimate the risk of VTE in patients with cancer but these have been validated in solid organ tumors. The records of patients with myeloma attending a university hospital between January 2007 and December 2012 were reviewed to investigate the incidence of VTE and the associated risk factors. In all, 217 patients with a mean (standard deviation) age at diagnosis of 65 (12) years were included. Of 217 patients, 12% had an episode of VTE, 69% received at least 1 immunomodulatory agent, and 95% had low or intermediate risk of VTE according to the Khorana score. Venous thromboembolism was a frequent occurrence in this cohort. Patients had many risk factors for VTE but no one was predictive. As myeloma outcomes continue to improve, a dedicated prospective study is warranted to investigate the most appropriate thromboprophylaxis strategy.

The 'carry-over' effects of patient self-testing: positive effects on usual care management by an anticoagulation management service.

INTRODUCTION: Patient self-testing (PST) of the international normalised ratio (INR) has a positive effect on anticoagulation control. This study investigated whether the benefits of PST (other than increased frequency of testing, e.g. patient education, empowerment, compliance etc.) could be 'carried-over' into usual care management after a period of home-testing has ceased. MATERIAL AND METHODS: Patients that completed a six month period of PST (as part of a randomised controlled trial) but returned to clinic management when the trial ended were included in the study. The primary outcome variable was the difference in anticoagulation control (measured using the time in therapeutic range) between the two periods. A group of patients who were managed solely by the anticoagulation clinic served as the control. RESULTS: There was no significant difference in median time in therapeutic range (TTR) between the 52 patients during clinic management post-PST and the six month period of PST (75% vs 75.3%; p=0.061). Patients tested more frequently while home-testing compared with the subsequent six month period of clinic management (once every 5.6±0.7days compared with once every 23.2±7.4days; p=0.000). Patients with previous experience of PST performed significantly better than the control group of patients (n=107) that were managed solely by the anticoagulation clinic (75% vs 59.7%; p=0.009) despite less frequent monitoring of the INR (every 23.2±7.4days vs. 17.4±6.7days; p=0.000). CONCLUSIONS: The improvements in anticoagulation control observed during a period of PST can be sustained when patients cease home-testing and revert back to usual care management.

Direct-to-patient expert system and home INR monitoring improves control of oral anticoagulation.

BACKGROUND AND OBJECTIVE: Internet-based disease management programs have the potential to improve patient care. The objective of this study was to determine whether an interactive, internet-based system enabling supervised, patient self-management of oral anticoagulant therapy provided management comparable to an established anticoagulation clinic. PATIENTS/METHODS: Sixty patients receiving chronic oral anticoagulant therapy who had access to the internet and a printer, were enrolled into this prospective, single-group, before-after study from a single clinic and managed between March 2002 and January 2003. Patients learned how to use a home prothrombin time monitor and how to access the system through the internet. Patients used the system for six months, with daily review by the supervising physician. The primary outcome variable was the difference in time in therapeutic range prior to and following introduction of internet-supervised patient self-management. RESULTS: The mean time in therapeutic range increased from 63% in the anticoagulation clinic (control period) to 74.4% during internet-supervised patient self-management (study period). The mean difference score between control and study periods was 11.4% (P = 0.004, 95% confidence interval 5.5-17.3%). There were no hemorrhagic or thromboembolic complications. CONCLUSIONS: This novel approach of internet-supervised patient self-management improved time in therapeutic range compared to an anticoagulation clinic. This is the first demonstration of an internet-based expert system enabling remote and effective management of patients on oral anticoagulants. Expert systems may be applicable for management of other chronic diseases.

A multi-dose pharmacokinetic study of dalteparin in haemodialysis patients.

Low-molecular-weight heparins undergo renal elimination, and therefore the proper dosing in hemodialysis (HD) patients is unclear. It was the objective of this study to evaluate the pharmacokinetic (PK) parameters of dalteparin in patients receiving chronic HD for end-stage renal disease. We performed a multidose PK study with prophylactic doses of dalteparin in twelve HD patients. Dalteparin 5,000 IU was administered subcutaneously daily for four consecutive days, with HD performed on day 2 and day 4. Anti-factor Xa activity was determined daily and at multiple blood samples after the 3rd and 4th dose. Eleven of 12 patients completed the study. The mean (range) PK parameters determined after the 4th dose were as follows: i) maximum concentration (Cmax ) was 0.31 IU/ml (0.06 to 0.55 IU/ml); ii) time to Cmax was 3.55 hours (2.59 to 4.96 hr); iii) area under the curve was 3.24 IU*hr/ml (0.64 to 6.44 IU*hr/ml); iv) half-life was 3.82 hr (2.03 to 9.63 hr); and v) trough anti-factor Xa activity 0.04 IU/ml (0.02 to 0.08 IU/ml). No major bleeding was observed. In general, patients with lower body weight exhibited a higher Cmax . From this pilot PK study, we have determined initial PK parameters for dalteparin in HD patients. Although a standard prophylactic dose was used, we found that in this patient population differences in body weight influenced the Cmax. Future studies to evaluate the PK parameters of dalteparin in patients receiving chronic HD may have to use weight-based dosing and will need to be performed over a longer period of time.

Anti-beta2 glycoprotein 1 and the anti-phospholipid syndrome.

PURPOSE: To describe a patient who presented with bilateral retinal vascular occlusion and the use of anti-beta2 glycoprotein 1 (GPI) antibody testing in the diagnosis of antiphospholipid syndrome. DESIGN: Observational case report. METHODS: Hematological investigations were performed on a 49-year-old man who presented with rapid onset of bilateral severe central retinal vein occlusion. RESULTS: Lupus anticoagulant and anticardiolipin antibody testing was negative. Markedly raised titers of anti-beta2 GPI antibodies were detected on two separate occasions. CONCLUSIONS: The raised titers of anti-beta2 GPI antibodies were considered to strongly suggest an underlying diagnosis of the antiphospholipid syndrome.

Management of lepirudin therapy for a patient with antiphospholipid antibody syndrome using the whole blood ecarin clot time and activated partial thromboplastin time.

A patient with antiphospholipid antibody syndrome (APS) and a history of heparin-induced thrombocytopenia required lepirudin therapy. The patient had an abnormal baseline activated partial thromboplastin time (aPTT), complicating management of his therapy. We investigated whether an alternative monitoring system, using a dry reagent technology [Thrombolytic Assessment System (TAS)], could be used to monitor the patient's whole blood ecarin clot time (ECT) and aPTT. Baseline values for the ECT and aPTT were normal with this system. During a continuous infusion of lepirudin, the patient's whole blood ECT was maintained between a desired range of 150-200 s for 73% of the time. Similarly, his whole blood aPTT was maintained between 60 and 80 s for 80% of the time. In contrast, the patient's plasma-based aPTT by standard methods was consistently > 150 s. The patient underwent surgical procedures without complications. To further investigate the finding that the patient's antibody did not affect the aPTT with this system, we performed the ECT and the aPTT assays on the TAS Analyzer with plasma samples from 10 patients with APS and abnormal aPTTs. All 10 samples had plasma ECT values within the normal range. Four patients had normalization of the aPTT, suggesting that a subset of patients with APS may benefit from the TAS aPTT assay when monitoring heparin or other anticoagulation therapy.