Research on the relationship between fibrinogen level and subtypes of the TOAST criteria in the acute ischemic stroke

Background

Cerebral infarction caused by different reasons seems differ in fibrinogen levels, so the current work intends to explore the relationship between the fibrinogen level and subtypes of the TOAST criteria in the acute stage of ischemic stroke.

Methods

A total of 577 case research objects were treated acute ischemic stroke patients in our hospital from December 2008 to December 2010, and blood samples within 72 hours of the onset were processed with the fibrinogen (PT-der) measurement. Classification of selected patients according to the TOAST Criteria was conducted to study the distribution of fibrinogen levels in the stroke subtypes.

Results

The distribution of fibrinogen levels in the subtypes was observed to be statistically insignificant.

Conclusions

In the acute stage of ischemic stroke, fibrinogen level was not related to the subtypes of the TOAST criteria.

     

Cerebral infarcts associated with adenomyosis: a rare risk factor for stroke in middle-aged women: a case series

Background

Adenomyosis is a benign disease with elevated CA125 level.

Case presentation

We report 3 cases with adenomyosis who developed ischemic stroke during menstruation. The levels of CA125, CA19–9, and D-dimer were elevated, which dropped markedly after the menstrual phase. The development of nonbacterial thrombotic endocarditis (NBTE) and stenosis of the cerebral arteries associated with hypercoagulable state and the hyperviscosity nature of the mucinous protein may be the underlying mechanisms.

Conclusion

Our report suggests that adenomyosis might be a risk factor for ischemic stroke in middle-aged patients.

     

Atrial fibrillation is not uncommon among patients with ischemic stroke and transient ischemic stroke in China

Background

Atrial fibrillation (AF) is reported to be a less frequent cause of ischemic stroke in China than in Europe and North America, but it is not clear whether this is due to underestimation. Our aim was to define the true frequency of AF-associated stroke, to determine the yield of 6-day Holter ECG to detect AF in Chinese stroke patients, and to elucidate predictors of newly detected AF.

Methods

Patients with acute ischemic stroke or transient ischemic attack (TIA) were enrolled in a prospective, multicenter cohort study of 6-day Holter monitoring within 7 days after stroke onset at 20 sites in China between 2013 and 2015. Independent predictors of newly-detected AF were determined by multivariate analysis.

Results

Among 1511 patients with ischemic stroke and TIA (mean age 63 years, 33.1% women), 305 (20.2%) had either previously known (196, 13.0%) or AF newly-detected by electrocardiography (53, 3.5%) or by 6-day Holter monitoring (56/1262, 4.4%). A history of heart failure (OR?=?4.70, 95%CI, 1.64–13.5), advanced age (OR?=?1.06, 95%CI, 1.04–1.09), NIHSS at admission (OR?=?1.06, 95%CI, 1.02–1.10), blood high density lipoprotein (HDL) (OR?=?1.52, 95%CI, 1.09–2.13), together with blood triglycerides (OR?=?0.64, 95%CI, 0.45–0.91) were independently associated with newly-detected AF.

Conclusions

Contrary to previous reports, AF-associated stroke is frequent (20%) in China if systemically sought. Prolonged noninvasive cardiac rhythm monitoring importantly increases AF detection in patients with recent ischemic stroke and TIA in China. Advanced age, history of heart failure, and higher admission NIHSS and higher level of HDL were independent indicators of newly-detected AF.

Trial registration

NCT02156765 (June 5, 2014).

     

A prospective cohort study of stroke characteristics,care, and mortality in a hospital stroke registry in Vietnam

Background

As low and middle-income countries such as Vietnam experience the health transition from infectious to chronic diseases, the morbidity and mortality from stroke will rise. In line with the recommendation of the Institute of Medicine’s report on “Promoting Cardiovascular Health in the Developing World” to “improve local data”, we sought to investigate patient characteristics and clinical predictors of mortality among stroke inpatients at Da Nang Hospital in Vietnam.

Methods

A stroke registry was developed and implemented at Da Nang Hospital utilizing the World Health Organization’s Stroke STEPS instrument for data collection.

Results

754 patients were hospitalized for stroke from March 2010 through February 2011 and admitted to either the intensive care unit or cardiology ward. Mean age was 65 years, and 39% were female. Nearly 50% of strokes were hemorrhagic. At 28-day follow-up, 51.0% of patients with hemorrhagic stroke died whereas 20.3% of patients with ischemic stroke died. A number of factors were independently associated with 28-day mortality; the two strongest independent predictors were depressed level of consciousness on presentation and hemorrhagic stroke type. While virtually all patients completed a CT during the admission, evidence-based processes of care such as anti-thrombotic therapy and carotid ultrasound for ischemic stroke patients were underutilized.

Conclusions

This cohort study highlights the high mortality due in part to the large proportion of hemorrhagic strokes in Vietnam. Lack of hypertension awareness and standards of care exacerbated clinical outcomes. Numerous opportunities for simple, inexpensive interventions to improve outcomes or reduce recurrent stroke have been identified.

     

A pilot study of rivastigmine in the treatment of delirium after stroke: A safe alternative

Background

Delirium is a common disorder in the early phase of stroke. Given the presumed cholinergic deficiency in delirium, we tested treatment with the acetylcholinesterase inhibitor rivastigmine.

Methods

This pilot study was performed within an epidemiological study. In 527 consecutive stroke patients presence of delirium was assessed during the first week with the confusion assessment method. Severity was scored with the delirium rating scale (DRS). Sixty-two patients developed a delirium in the acute phase of stroke. Only patients with a severe and persistent delirium (defined as a DRS of 12 or more for more than 24 hours) were enrolled in the present study. In total 26 fulfilled these criteria of whom 17 were treated with orally administered rivastigmine with a total dose between 3 and 12 mg a day. Eight patients could not be treated because of dysphagia and one because of early discharge.

Results

No major side effects were recorded. In 16 patients there was a considerable decrease in severity of delirium. The mean DRS declined from 14.8 on day one to 8.5 after therapy and 5.6 after tapering. The mean duration of delirium was 6.7 days (range; 2–17).

Conclusion

Rivastigmine is safe in stroke patients with delirium even after rapid titration. In the majority of patients the delirium improved after treatment. A randomized controlled trial is needed to establish the usefulness of rivastigmine in delirium after stroke.

Trial registration

Nederlands Trial Register NTR1395

     

Predictors of post-stroke body temperature elevation

Background

Growing evidence indicates that elevated body temperature after stroke is associated with unfavorable outcome. The aim of the current study was to investigate which factors predict temperature elevation within 48 h of stroke onset. Specifically, we hypothesized that temperature elevation would be associated with stroke symptom severity and that hemorrhagic stroke would cause a more pronounced temperature increase compared to ischemic stroke.

Methods

The medical records of 400 stroke patients were retrospectively reviewed. Multiple linear regression analysis was used to determine which factors were associated with elevated body temperature.

Results

Several factors were significantly associated with peak body temperature (the highest recorded body temperature) within 48 h of stroke onset: stroke severity measured by the National Institutes of Health Stroke Scale (NIHSS) (regression coefficient; (RC) 0.022), female gender (RC 0.157), tympanic/non-rectal temperature reading (RC ?0.265), swallowing difficulties (RC 0.335), intubation (RC 0.470), antipyretic treatment (RC 0.563), and C-reactive protein?>?50 or signs of infection at admission (RC 0.298). Contrary to our expectations, patients with intracerebral hemorrhage did not have higher peak body temperatures than patients with ischemic stroke.

Conclusions

In conclusion, temperature elevation within the first 48 h of stroke onset is common, can be partially predicted using information at admission and is strongly associated with stroke severity. The strong association with stroke severity may, at least partly, explain the previously described association between post-stroke temperature elevation and unfavorable outcome.

     

Carotid plaque rather than intima-media thickness as a predictor of recurrent vascular events in patients with acute ischemic stroke

Background

To investigate the impacts of carotid plaque and intima-media thickness (IMT) on future vascular events (VEs) in the patients with acute ischemic stroke.

Methods

A total of 479 consecutive Korean patients with acute ischemic stroke were divided into 2 groups according to development of VEs; VE group (65.4 ± 10.9 years) vs no VE group (62.8 ± 13.2 years). VEs were defined as the development of recurrent stroke, coronary events, peripheral arterial disease, and death. Clinical, laboratory, and imaging findings were compared between the groups.

Results

During 105.5 ± 29.0 months of follow up, VEs were developed in 142 patients (29.6%). In univariate analysis, VEs were significantly associated with age, gender, diabetes, renal function, lipid levels, left ventricular function, carotid plaque or IMT. In multivariate analysis, the presence of carotid plaque, diabetes, renal function and male gender were independent predictors of future VEs in the patients with ischemic stroke, but carotid IMT was not a predictor of future VEs. Event free survival was significantly lower in patients with carotid plaque than without carotid plaque on Kaplan-Meier analysis (log rank p < 0.001).

Conclusion

The present study demonstrated that diabetes, impaired renal function, male gender, and the presence of carotid plaque rather than IMT were independent predictors of future VEs in Korean patients with acute ischemic stroke. Active medical management and careful monitoring for the development of recurrent VEs are strongly recommended in patients with acute ischemic stroke and carotid plaque.

     

Ischemic stroke incidence in Santa Coloma de Gramenet (ISISCOG), Spain. A community-based study

Background

In Spain, stroke is one of the major causes of death and the main cause of severe disability in people over 65 years. We analyzed the incidence of ischemic stroke, stroke subtypes, case fatality and disability at 90 days after the event in a Spanish population.

Methods

A prospective community-based register of ischemic strokes was established in Santa Coloma de Gramenet (Barcelona) [116,220 inhabitants of all ages, according to the municipal census of December 31,2001], from January 1 to December 31, 2003.Standard definitions and case finding methods were used to identify all cases in all age groups. Every patient underwent a complete clinical evaluation and systematic tests including neuroimaging (CT/MRI) and vascular studies (carotid duplex ultrasound intra and extracranial and MR angiography).

Results

Over a one year period, 196 ischemic strokes were registered [107 men; median age = 76 years (range 39–98)], being the first event in 159 patients (81.1%) and a recurrent stroke in 37 (18.9%). After age-adjustment to the European population, the incidence of ischemic stroke per 100,000 inhabitants was 172 (95% CI, 148–196); 219 (176–261) in men and 133 (105–160) in women, with an annual incidence for first ischemic stroke of 139 (118–161); 165 (128–201) in men and 115 (89–140) in women. The incidence of stroke increased with age.Stroke subtypes (TOAST classification criteria) were lacunar in 28.8%, atherothrombotic in 18.6%, cardioembolic in 26.6% and undetermined in 26.0% of patients. At 90 days, the case-fatality was 12%, and among survivors, moderate-to-severe disability was present in 45 % at 3 months.

Conclusion

This prospective community-based study shows one of the lowest incidences of stroke in Europe, as well as one of the lowest case fatality and disability rates at 90 days after stroke.

     

The carotid plaque imaging in acute stroke (CAPIAS) study: protocol and initial baseline data

Background

In up to 30% of patients with ischemic stroke no definite etiology can be established. A significant proportion of cryptogenic stroke cases may be due to non-stenosing atherosclerotic plaques or low grade carotid artery stenosis not fulfilling common criteria for atherothrombotic stroke. The aim of the CAPIAS study is to determine the frequency, characteristics, clinical and radiological long-term consequences of ipsilateral complicated American Heart Association lesion type VI (AHA-LT VI) carotid artery plaques in patients with cryptogenic stroke.

Methods/Design

300 patients (age >49 years) with unilateral DWI-positive lesions in the anterior circulation and non- or moderately stenosing (<70% NASCET) internal carotid artery plaques will be enrolled in the prospective multicenter study CAPIAS. Carotid plaque characteristics will be determined by high-resolution black-blood carotid MRI at baseline and 12 month follow up. Primary outcome is the prevalence of complicated AHA-LT VI plaques in cryptogenic stroke patients ipsilateral to the ischemic stroke compared to the contralateral side and to patients with defined stroke etiology. Secondary outcomes include the association of AHA-LT VI plaques with the recurrence rates of ischemic events up to 36 months, rates of new ischemic lesions on cerebral MRI (including clinically silent lesions) after 12 months and the influence of specific AHA-LT VI plaque features on the progression of atherosclerotic disease burden, on specific infarct patterns, biomarkers and aortic arch plaques.

Discussion

CAPIAS will provide important insights into the role of non-stenosing carotid artery plaques in cryptogenic stroke. The results might have implications for our understanding of stroke mechanism, offer new diagnostic options and provide the basis for the planning of targeted interventional studies.

Trial Registration

NCT01284933

     

Secondary pallidonigral degeneration mimicking recurrent acute stroke in clinical presentation and magnetic resonance imaging: a case report

Background

Secondary pallidonigral transneuronal degeneration after a remote primary cerebral infarct can mimic recurrent stroke at clinical presentation. We describe a patient with secondary pallidonigral degeneration following a previous putaminal infarct, which was diagnosed through diffusion-weighted (DWI) and T2-weighted imaging (T2WI).

Case presentation

A 64-year-old man complained of an acute relapse of right-lower-limb weakness following a cerebral infarction 2 months before presentation. Recurrent cerebral stroke was initially diagnosed in the emergency room. DWI of the brain revealed a subacute to chronic infarct in the left putamen and new acute cytotoxic edema in the left substantia nigra (SN) and globus pallidus while T2WI also showed hyperintensity in the same regions. The SN was outside the aforementioned middle cerebral arterial territory, which includes the putamen. These findings are compatible with the diagnosis of acute pallidonigral injury secondary to striatal infarction. The patient had fully recovered from his right-lower-limb weakness after 1 month.

Conclusions

Secondary pallidonigral degeneration may mimic recurrent stroke. DWI along with T2WI facilitates elucidation of this clinicopathological entity, and thus unnecessary treatment can be avoided.

     

Exploratory screening for Fabry’s disease in young adults with cerebrovascular disorders in northern Sardinia

Background

The etiologic determinants of stroke in young adults remain a diagnostic challenge in up to one-fourth of cases. Increasing evidences led to consider Fabry’s disease (FD) as a possible cause to check up. We aimed at evaluating the prevalence of unrecognized FD in a cohort of patients with juvenile stroke in northern Sardinia.

Methods

For this study, we enrolled 178 patients consecutively admitted to our Neurological Ward for ischemic stroke, transient ischemic attack, intracerebral haemorrhage, neuroradiological evidence of silent infarcts, or white matter lesions possibly related to cerebral vasculopathy at brain MRI, and cerebral venous thrombosis. The qualifying events have to occur between 18 and 55 years of age.

Results

We identified two patients with an α-galactosidase A gene variant, with a prevalence of 0.9 %. According to recent diagnostic criteria, one patient, included for the occurrence of multiple white matter lesions at brain MRI, had a diagnosis of definite FD, the other, included for ischemic stroke, had a diagnosis of uncertain FD.

Conclusions

Our study places in a middle position among studies that found a prevalence of FD up to 4 % and others that did not find any FD patients. Our findings confirm that FD should be considered in the differential diagnosis of patients with juvenile stroke, particularly those with a personal or familial history positive for cerebrovascular events, or evidence of combined cardiologic and/or renal impairment. All types of cerebrovascular disorders should be screened for FD, including patients with white matter lesions possibly related to cerebral vasculopathy at brain MRI.

     

Effectiveness of revascularization of the ulcerated foot in diabetic patients with peripheral artery disease for one year follow-up

Background

Diabetes is an important risk factor for atherosclerosis. The diabetic foot is characterized by the presence of arteriopathy and neuropathy. When ischemia is diagnosed, restoration of pulsatile blood flow by revascularization may be considered for salvaging the limb. The treatment options are angioplasty with or without stenting and surgical bypass or hybrid procedures combining the two.

Aims

To evaluate the outcomes of severe ischemic diabetic foot ulcers for which percutaneous transluminal angioplasty (PTA) was considered as the first-line vascular procedure. Factors associated with successful PTA were also evaluated.

Methods

In 80 consecutive diabetic patients with foot ulcers and severe limb ischemia, PTAwas performed if feasible. All patients were followed until healing or for one year. Clinical and angiographic factors in fluencing outcomes after PTA were sought by univariate and multivariate analysis.

Results

PTAwas done in 73 of the 80 (91.2%) patients, and considered clinically succe ssful in 58(79.9%). Successful PTA was significantly higher in patients with Superficial femoral artery, posterior Tibialis and dorsalis pedis arteries involvement in the univariate analysis. Seven patients were expired during the study follow up due to MI, pulmonary thromboembolism and GI bleeding.

Conclusion

PTA in diabetic patients with severe ischemic foot ulcers provided favorable. Some parameters could be used for predicting PTA successfulness.

     

Multimodal pressure-flow method to assess dynamics of cerebral autoregulation in stroke and hypertension

Background

This study evaluated the effects of stroke on regulation of cerebral blood flow in response to fluctuations in systemic blood pressure (BP). The autoregulatory dynamics are difficult to assess because of the nonstationarity and nonlinearity of the component signals.

Methods

We studied 15 normotensive, 20 hypertensive and 15 minor stroke subjects (48.0 ± 1.3 years). BP and blood flow velocities (BFV) from middle cerebral arteries (MCA) were measured during the Valsalva maneuver (VM) using transcranial Doppler ultrasound.

Results

A new technique, multimodal pressure-flow analysis (MMPF), was implemented to analyze these short, nonstationary signals. MMPF analysis decomposes complex BP and BFV signals into multiple empirical modes, representing their instantaneous frequency-amplitude modulation. The empirical mode corresponding to the VM BP profile was used to construct the continuous phase diagram and to identify the minimum and maximum values from the residual BP (BP_R) and BFV (BFV_R) signals. The BP-BFV phase shift was calculated as the difference between the phase corresponding to the BP_R and BFV_R minimum (maximum) values. BP-BFV phase shifts were significantly different between groups. In the normotensive group, the BFV_R minimum and maximum preceded the BP_R minimum and maximum, respectively, leading to large positive values of BP-BFV shifts.

Conclusion

In the stroke and hypertensive groups, the resulting BP-BFV phase shift was significantly smaller compared to the normotensive group. A standard autoregulation index did not differentiate the groups. The MMPF method enables evaluation of autoregulatory dynamics based on instantaneous BP-BFV phase analysis. Regulation of BP-BFV dynamics is altered with hypertension and after stroke, rendering blood flow dependent on blood pressure.

     

Pharmacological targeting of secondary brain damage following ischemic or hemorrhagic stroke,traumatic brain injury,and bacterial meningitis - a systematic review and meta-analysis

Background

The effectiveness of pharmacological strategies exclusively targeting secondary brain damage (SBD) following ischemic stroke, aneurysmal subarachnoid hemorrhage, aSAH, intracerebral hemorrhage (ICH), traumatic brain injury (TBI) and bacterial meningitis is unclear. This meta-analysis studied the effect of SBD targeted treatment on clinical outcome across the pathological entities.

Methods

Randomized, controlled, double-blinded trials on aforementioned entities with ‘death’ as endpoint were identified. Effect sizes were analyzed and expressed as pooled risk ratio (RR) estimates with 95% confidence intervals (CI). 123 studies fulfilled the criteria, with data on 66,561 patients.

Results

In the pooled analysis, there was a minor reduction of mortality for aSAH [RR 0.93 (95% CI:0.85–1.02)], ICH [RR 0.92 (95% CI:0.82–1.03)] and bacterial meningitis [RR 0.86 (95% CI:0.68–1.09)]. No reduction of mortality was found for ischemic stroke [RR 1.05 (95% CI:1.00–1.11)] and TBI [RR 1.03 (95% CI:0.93–1.15)]. Additional analysis of “poor outcome” as endpoint gave similar results. Subgroup analysis with respect to effector mechanisms showed a tendency towards a reduced mortality for the effector mechanism category “oxidative metabolism/stress” for aSAH with a risk ratio of 0.86 [95% CI: 0.73–1.00]. Regarding specific medications, a statistically significant reduction of mortality and poor outcome was confirmed only for nimodipine for aSAH and dexamethasone for bacterial meningitis.

Conclusions

Our results show that only a few selected SBD directed medications are likely to reduce the rate of death and poor outcome following aSAH, and bacterial meningitis, while no convincing evidence could be found for the usefulness of SBD directed medications in ischemic stroke, ICH and TBI. However, a subtle effect on good or excellent outcome might remain undetected. These results should lead to a new perspective of secondary reactions following cerebral injury. These processes should not be seen as suicide mechanisms that need to be fought. They should be rather seen as well orchestrated clean-up mechanisms, which may today be somewhat too active in a few very specific constellations, such as meningitis under antibiotic treatment and aSAH after surgical or endovascular exclusion of the aneurysm.

     

Optimization of fecal sample preparation for untargeted LC-HRMS based metabolomics

Introduction

Collecting feces is easy. It offers direct outcome to endogenous and microbial metabolites.

Objectives

In a context of lack of consensus about fecal sample preparation, especially in animal species, we developed a robust protocol allowing untargeted LC-HRMS fingerprinting.

Methods

The conditions of extraction (quantity, preparation, solvents, dilutions) were investigated in bovine feces.

Results

A rapid and simple protocol involving feces extraction with methanol (1/3, M/V) followed by centrifugation and a step filtration (10 kDa) was developed.

Conclusion

The workflow generated repeatable and informative fingerprints for robust metabolome characterization.

     

Pseudo current density maps of electrophysiological heart,nerve or brain function and their physical basis

Background

In recent years the visualization of biomagnetic measurement data by so-called pseudo current density maps or Hosaka-Cohen (HC) transformations became popular.

Methods

The physical basis of these intuitive maps is clarified by means of analytically solvable problems.

Results

Examples in magnetocardiography, magnetoencephalography and magnetoneurography demonstrate the usefulness of this method.

Conclusion

Hardware realizations of the HC-transformation and some similar transformations are discussed which could advantageously support cross-platform comparability of biomagnetic measurements.

     

The Association Between Depression,Suicidal Ideation and Psychological Strains in College Students: A Cross-National Study

Objective

This study examined the differences of psychological strains between Chinese and American college students and discussed how strains may influence individuals’ suicidal ideation and depression.

Participants/methods

A total of 539 college students (298 from China and 241 from the U.S.) were recruited in March 2016 to complete the survey study. Multiple linear regressions were used in data analysis.

Results

Students in America had higher scores on depression and stress than students in China, while students in China rated higher on suicidal ideation than students in America. In contrast of students in America facing more coping strains, students in China were confronting more value strains in their life.

Conclusion

The cross-cultural variations in the effect of psychological strains have been substantiated in current study, indicating that understanding the psychological strains in different cultural contexts is necessary for the early intervention and prevention in college aged populations.

     

A lost opportunity for science: journals promote data sharing in metabolomics but do not enforce it

Introduction

Data sharing is being increasingly required by journals and has been heralded as a solution to the ‘replication crisis’.

Objectives

(i) Review data sharing policies of journals publishing the most metabolomics papers associated with open data and (ii) compare these journals’ policies to those that publish the most metabolomics papers.

Methods

A PubMed search was used to identify metabolomics papers. Metabolomics data repositories were manually searched for linked publications.

Results

Journals that support data sharing are not necessarily those with the most papers associated to open metabolomics data.

Conclusion

Further efforts are required to improve data sharing in metabolomics.

     

Periprocedural heparin bridging in patients receiving oral anticoagulation: a systematic review and meta-analysis

Background

Periprocedural heparin bridging therapy aims to reduce the risk of thromboembolic events in patients requiring an interruption in their anticoagulation therapy for the purpose of an elective procedure. The efficacy and safety of heparin bridging therapy has not been well established.

Objectives

To compare through meta-analysis the effects of heparin bridging therapy on the risk of major bleeding and thromboembolic events of clinical significance among patients taking oral anticoagulants.

Methods

We searched PubMed, EMBASE and the Cochrane library from January 2005 to July 2016. Studies were included if they reported clinical outcomes of patients receiving heparin bridging therapy during interruption of oral anticoagulant for operations. Data were pooled using random-effects modeling.

Results

A total of 25 studies, including 6 randomized controlled trials and 19 observational studies, were finally included in this analysis. Among all the 35,944 patients, 10,313 patients were assigned as heparin bridging group, and the other 25,631 patients were non-heparin bridging group. Overall, compared with patients without bridging therapy, heparin bridging therapy increased the risk of major bleeding (OR?=?3.23, 95%CI: 2.06–5.05), minor bleeding (OR?=?1.52, 95%CI: 1.06–2.18) and overall bleeding (OR?=?2.83, 95%CI: 1.86–4.30).While there was no significant difference in thromboembolic events (OR?=?0.99,95%CI: 0.49–2.00), stroke or transient ischemic attack(OR?=?1.45, 95%CI: 0.93–2.26,) or all-cause mortality (OR?=?0.71, 95%CI: 0.31–1.65).

Conclusions

Heparin-bridging therapy increased the risk of major and minor bleeding without decreasing the risk of thromboembolic events and all cause death compared to non-heparin bridging.