Telangiectatic Matting is Associated with Hypersensitivity and a Bleeding Tendency.

OBJECTIVE: The aim was to investigate the pathogenesis of telangiectatic matting (TM) and identify possible risk factors. METHODS: This study had two parts. The clinical records of consecutive patients were retrospectively analysed to identify risk factors for TM. In the second part, the haemostatic and coagulation profile of the subset of patients with TM were analysed and compared with controls using standard coagulation tests, platelet function and a global assay of coagulation (rotational thromboelastometry, ROTEM). RESULTS: In 352 consecutive patients presenting to a phlebology practice, 25 patients had TM (7.1%). All 25 patients were female with the median age of 45 (27-57) years. A comprehensive medical history was taken. Among 27 possible risk factors assessed, statistically significant associations included recurrent epistaxis, easy bruising, hypersensitivity (eczema, hives, hay fever, and rhinitis), previous treatment with sclerotherapy or endovenous laser for lower limb veins, and a family history of telangiectasias. Variables not associated with TM included oral contraceptive intake, hormone replacement therapy, and age. The haemostatic and coagulation profile of 12 patients (6 male and 6 female) with TM did not differ significantly from those without TM. CONCLUSION: TM is associated with both hypersensitivity and a bleeding tendency. This study revealed no significant increase in the incidence of haemostatic abnormalities in patients with TM compared with the control group. Given the significant association with hypersensitivity disorders, the underlying mast cell hyper-reactivity may contribute to both hypersensitivity and a bleeding tendency and predispose patients to TM.

Variations in the cerebrospinal fluid proteome following traumatic brain injury and subarachnoid hemorrhage.

BACKGROUND: Proteomic analysis of cerebrospinal fluid (CSF) has shown great promise in identifying potential markers of injury in neurodegenerative diseases [1-13]. Here we compared CSF proteomes in healthy individuals, with patients diagnosed with traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) in order to characterize molecular biomarkers which might identify these different clinical states and describe different molecular mechanisms active in each disease state. METHODS: Patients presenting to the Neurosurgery service at the Louisiana State University Hospital-Shreveport with an admitting diagnosis of TBI or SAH were prospectively enrolled. Patients undergoing CSF sampling for diagnostic procedures were also enrolled as controls. CSF aliquots were subjected to 2-dimensional gel electrophoresis (2D GE) and spot percentage densities analyzed. Increased or decreased spot expression (compared to controls) was defined in terms of in spot percentages, with spots showing consistent expression change across TBI or SAH specimens being followed up by Matrix-Assisted Laser Desorption/Ionization mass spectrometry (MALDI-MS). Polypeptide masses generated were matched to known standards using a search of the NCBI and/or GenPept databases for protein matches. Eight hundred fifteen separately identifiable polypeptide migration spots were identified on 2D GE gels. MALDI-MS successfully identified 13 of 22 selected 2D GE spots as recognizable polypeptides. RESULTS: Statistically significant changes were noted in the expression of fibrinogen, carbonic anhydrase-I (CA-I), peroxiredoxin-2 (Prx-2), both α and ß chains of hemoglobin, serotransferrin (Tf) and N-terminal haptoglobin (Hp) in TBI and SAH specimens, as compared to controls. The greatest mean fold change among all specimens was seen in CA-I and Hp at 30.7 and -25.7, respectively. TBI specimens trended toward greater mean increases in CA-I and Prx-2 and greater mean decreases in Hp and Tf. CONCLUSIONS: Consistent CSF elevation of CA-I and Prx-2 with concurrent depletion of Hp and Tf may represent a useful combination of biomarkers for the prediction of severity and prognosis following brain injury.

Effects of antiplatelet therapy on platelet extracellular vesicle release and procoagulant activity in health and in cardiovascular disease.

Dual antiplatelet therapy with aspirin and clopidogrel is commonly used to prevent recurrent ischemic events in patients with cardiovascular disease. Whilst their effects on platelet reactivity are well documented, it is unclear, however, whether antiplatelet therapy inhibits platelet extracellular vesicle (EV) release. The aim of this study was to investigate the effects of antiplatelet therapy on platelet EV formation and procoagulant activity. Blood samples from 10 healthy controls not receiving antiplatelet therapy were incubated in vitro with aspirin or a P2Y12 inhibitor (MeSAMP). Blood samples from 50 patients receiving long-term dual antiplatelet therapy and undergoing coronary angiography were also studied. Platelet reactivity was assessed by Multiplate™ impedance aggregometry. Platelet EV formation and procoagulant activity of pretreated and untreated blood samples in response to arachidonic acid (AA), adenosine diphosphate (ADP), ADP+PGE1, and thrombin receptor-activating peptide (TRAP) stimulation were assessed by flow cytometry and Procoag-PL assays, respectively. Incubation of normal platelets with aspirin significantly inhibited AA-induced platelet reactivity, EV formation, and procoagulant activity, whilst MeSAMP significantly inhibited platelet reactivity and EV formation in response to AA, ADP, and TRAP, but had minimal effect on procoagulant activity. Most patients receiving dual antiplatelet therapy showed an appropriate reduction in platelet reactivity in response to their treatment; however there was not complete inhibition of increased platelet and EV procoagulant activity in response to ADP, AA, or TRAP. In addition, we could not find any correlation between platelet reactivity and procoagulant activity in patients receiving dual antiplatelet therapy.

Elucidating the utility of neuro-navigation in reducing malposition rates in Ommaya reservoir placement: 23-year operative experience at the Louisiana State University.

OBJECTIVES: Variability exists with the use of neuro-navigation in the placement of Ommaya reservoir. In the setting of recent healthcare reforms in the United States that are focused on cost-containment strategies, we discuss from our experience at the Louisiana State University, Shreveport, if the use of high-cost stealth-guided navigation technique reduces malposition rates over free-hand placement. PATIENTS AND METHODS: A retrospective cohort analyses on 146 patients that underwent placement of Ommaya reservoir between 1991 and 2014 using free-hand and neuro-navigated technique was performed. Primary endpoint was to evaluate the differences in rates of malposition across these two placement techniques. RESULTS: The mean age of our cohort was 44.85 ± 15.05 years and 45% patients were female. We did not find any statistical differences for complications rates including infections (8.3% vs 9.2%; P = 1.000), hemorrhage (0.0% vs 3.1%; P = 0.551), and repositioning (6.3% vs 8.2%; P = 1.000) across patients that underwent placement of Ommaya reservoir using neuro-navigation and free hand technique. CONCLUSION: Although placement of Ommaya reservoir is a relatively easier technique as compared to other neurosurgical procedures, based on our experience and literature, we found lower rates of complications in patients who underwent placement via the stealth-guided neuro-navigational approach. Despite not having found any statistical difference in malposition rates between navigated and free-hand implantation of Ommaya reservoirs in our series, it is plausible that the number of technical complications in the neuronavigational group in the early years of acquisition could possibly be attributed to the learning curve, rather than their occuring purely by chance. Nevertheless, considering the increased cost of hospitalization associated with the use of navigational technology, future studies are recommended to weigh the cost-benefit ratio of preferring the neuro-navigational techniques for placement of Ommaya reservoir over the free-hand placement techniques.

Factors predictive of improved overall survival following stereotactic radiosurgery for recurrent glioblastoma.

The currently accepted standard of care for primary glioblastoma (GBM) consists of maximal surgical resection followed by fractionated external beam radiotherapy (EBRT) with concomitant temozolomide chemotherapy. The role of stereotactic radiosurgery (SRS) in the treatment of GBM is not well defined, but SRS has typically been applied as a salvage therapy for GBM recurrence. This paper reviews our single institution experience using gamma knife radiosurgery (GKRS) for the treatment of GBM. Thirty-six patients treated with GKRS for pathologically proven GBM at LSU Health in Shreveport from February 2000 to December 2013 were identified and analyzed. Patient characteristics, treatment variables, and survival were correlated. Seven patients received GKRS in the immediate postoperative period for an average tumor volume of 10.9 cm(3), and 29 patients were treated for a recurrent average tumor volume of 11.4 cm(3) with a prescribed dose ranging from 10 to 20 Gy at the 50 % isodose line. The median overall survival was significantly higher in recurrence group compared to up-front group [7.9 months (0.77-32.1 months) vs. 3.5 months (range 0.23-11.7 months) respectively, (p = 0.018)]. The predictive factors for improved survival in the patients with GBM were as follows: Karnofsky performance scale (KPS) > 70 (p = 0.026), age ≤ 50 years (p = 0.006), absence of neurodeficits (p = 0.01), and initial postoperative treatment with EBRT (p = 0.042). Adjuvant therapy with GKRS following GBM recurrence demonstrates statistical superiority over immediate postoperative boost therapy.

A comparison of lumboperitoneal and ventriculoperitoneal shunting for idiopathic intracranial hypertension: an analysis of economic impact and complications using the Nationwide Inpatient Sample.

OBJECT: Complications following lumboperitoneal (LP) shunting have been reported in 18% to 85% of cases. The need for multiple revision surgeries, development of iatrogenic Chiari malformation, and frequent wound complications have prompted many to abandon this procedure altogether for the treatment of idiopathic benign intracranial hypertension (pseudotumor cerebri), in favor of ventriculoperitoneal (VP) shunting. A direct comparison of the complication rates and health care charges between first-choice LP versus VP shunting is presented. METHODS: The Nationwide Inpatient Sample database was queried for all patients with the diagnosis of benign intracranial hypertension (International Classification of Diseases, Ninth Revision, code 348.2) from 2005 to 2009. These data were stratified by operative intervention, with demographic and hospitalization charge data generated for each. RESULTS: A weighted sample of 4480 patients was identified as having the diagnosis of idiopathic intracranial hypertension (IIH), with 2505 undergoing first-time VP shunt placement and 1754 undergoing initial LP shunt placement. Revision surgery occurred in 3.9% of admissions (n = 98) for VP shunts and in 7.0% of admissions (n = 123) for LP shunts (p < 0.0001). Ventriculoperitoneal shunts were placed at teaching institutions in 83.8% of cases, compared with only 77.3% of first-time LP shunts (p < 0.0001). Mean hospital length of stay (LOS) significantly differed between primary VP (3 days) and primary LP shunt procedures (4 days, p < 0.0001). The summed charges for the revisions of 92 VP shunts ($3,453,956) and those of the 6 VP shunt removals ($272,484) totaled $3,726,352 over 5 years for the study population. The summed charges for revision of 70 LP shunts ($2,229,430) and those of the 53 LP shunt removals ($3,125,569) totaled $5,408,679 over 5 years for the study population. CONCLUSIONS: The presented results appear to call into question the selection of LP shunt placement as primary treatment for IIH, as this procedure is associated with a significantly greater likelihood of need for shunt revision, increased LOS, and greater overall charges to the health care system.

899 serious adverse events including 13 deaths, 7 strokes, 211 thromboembolic events, and 482 immune reactions: The untold story of cyanoacrylate adhesive closure.

OBJECTIVE: The aim was to retrieve and analyse the serious adverse events of venous occlusion systems used in cyanoacrylate adhesive closure (CAC) submitted to regulatory agencies. METHODS: The Total Product Life Cycle (TPLC) database of the US Food and Drug Administration (FDA), the Database of Adverse Event Notifications (DAEN) of the Australian Therapeutic Goods Administration (TGA), and the Yellow Card database of the UK Medicines and Healthcare Products Regulatory Agency (MHRA) were reviewed. Three Freedom of Information (FOI) requests had to be submitted to the MHRA to obtain data. RESULTS: The TPLC contained 899 reports which included 13 cases of death, 7 strokes, 211 thromboembolic events, and 482 immune reactions. The DAEN recorded three reportable adverse events, and the MHRA recorded seven adverse incidents including one death. CONCLUSION: CAC is associated with serious adverse events including death. These events are under-reported in the medical literature and only sub-optimally reported to the regulatory agencies.

Diagnosis of post-thrombotic syndrome: International union of phlebology (UIP) survey of medical specialists.

OBJECTIVE: To review the current approaches to the diagnosis of Post-Thrombotic Syndrome (PTS) and to evaluate the potential need for a diagnostic tool. METHOD: Medical specialists were invited to participate in an online survey of their current approaches to the diagnosis and management of PTS, including the use of scoring systems, diagnostic imaging techniques and the extent the practitioner reviews the patient's venous history. RESULTS: 502 participants completed the survey. Over 80% obtained imaging reports to confirm a history of deep vein thrombosis (DVT). 72% of participants always obtained an up-to-date duplex ultrasound for PTS diagnosis. Over 50% did not use a scoring system for either PTS diagnosis or management. 65% of the participants agreed that a new system for PTS diagnosis should be devised. CONCLUSION: Heterogeneity was observed in methods of diagnosing PTS by medical practitioners with frequent use of medical imaging studies and moderate use of scoring systems. Development of a new diagnostic tool for PTS should be considered for future studies.

Sclerotherapy of lower limb veins: Indications, contraindications and treatment strategies to prevent complications - A consensus document of the International Union of Phlebology-2023.

BACKGROUND: Sclerotherapy is a non-invasive procedure commonly used to treat superficial venous disease, vascular malformations and other ectatic vascular lesions. While extremely rare, sclerotherapy may be complicated by serious adverse events. OBJECTIVES: To categorise contraindications to sclerotherapy based on the available scientific evidence. METHODS: An international, multi-disciplinary panel of phlebologists reviewed the available scientific evidence and developed consensus where evidence was lacking or limited. RESULTS: Absolute Contraindications to sclerotherapy where the risk of harm would outweigh any benefits include known hypersensitivity to sclerosing agents; acute venous thromboembolism (VTE); severe neurological or cardiac adverse events complicating a previous sclerotherapy treatment; severe acute systemic illness or infection; and critical limb ischaemia. Relative Contraindications to sclerotherapy where the potential benefits of the proposed treatment would outweigh the risk of harm or the risks may be mitigated by other measures include pregnancy, postpartum and breastfeeding; hypercoagulable states with risk of VTE; risk of neurological adverse events; risk of cardiac adverse events and poorly controlled chronic systemic illness. Conditions and circumstances where Warnings and Precautions should be considered before proceeding with sclerotherapy include risk of cutaneous necrosis or cosmetic complications such as pigmentation and telangiectatic matting; intake of medications such as the oral contraceptive and other exogenous oestrogens, disulfiram and minocycline; and psychosocial factors and psychiatric comorbidities that may increase the risk of adverse events or compromise optimal treatment outcomes. CONCLUSIONS: Sclerotherapy can achieve safe clinical outcomes provided that (1) patient-related risk factors and in particular all material risks are (1a) adequately identified and the risk benefit ratio is clearly and openly discussed with treatment candidates within a reasonable timeframe prior to the actual procedure; (1b) when an individual is not a suitable candidate for the proposed intervention, conservative treatment options including the option of 'no intervention as a treatment option' are discussed; (1c) complex cases are referred for treatment in controlled and standardised settings and by practitioners with more expertise in the field; (1d) only suitable individuals with no absolute contraindications or those with relative contraindications where the benefits outweigh the risks are offered intervention; (1e) if proceeding with intervention, appropriate prophylactic measures and other risk-mitigating strategies are adopted and appropriate follow-up is organised; and (2) procedure-related risk factors are minimised by ensuring the treating physicians (2a) have adequate training in general phlebology with additional training in duplex ultrasound, procedural phlebology and in particular sclerotherapy; (2b) maintain their knowledge and competency over time and (2c) review and optimise their treatment strategies and techniques on a regular basis to keep up with the ongoing progress in medical technology and contemporary scientific evidence.

Vagal nerve stimulation for the treatment of medically refractory epilepsy: a review of the current literature.

OBJECT: The authors conducted a study to evaluate the published results of vagal nerve stimulation (VNS) for medically refractory seizures according to evidence-based criteria. METHODS: The authors performed a review of available literature published between 1980 and 2010. Inclusion criteria for articles included more than 10 patients evaluated, average follow-up of 1 or more years, inclusion of medically refractory epilepsy, and consistent preoperative surgical evaluation. Articles were divided into 4 classes of evidence according to criteria established by the American Academy of Neurology. RESULTS: A total of 70 publications were reviewed, of which 20 were selected for review based on inclusion and exclusion criteria. There were 2 articles that provided Class I evidence, 7 that met criteria for Class II evidence, and 11 that provided Class III evidence. The majority of evidence supports VNS usage in partial epilepsy with a seizure reduction of 50% or more in the majority of cases and freedom from seizure in 6%-27% of patients who responded to stimulation. High stimulation with a gradual increase in VNS stimulation over the first 6 weeks to 3 months postoperatively is well supported by Class I and II data. Predictors of positive response included absence of bilateral interictal epileptiform activity and cortical malformations. CONCLUSIONS: Vagal nerve stimulation is a safe and effective alternative for adult and pediatric populations with epilepsy refractory to medical and other surgical management.

Dr. Otto "Tiger" Freer: inventor and innovator.

Every neurosurgeon develops his or her own standard approach to common intracranial pathologies in terms of the order in which different stages are performed and which instruments are used to perform individual tasks. The majority of the basic steps in performing a craniotomy are learned through repetition and practice during residency training. Significant amounts of energy are devoted to mastering technical skills and developing an operative rhythm. What often receives little attention is the historical origin of the instruments that make the work possible. The Freer elevator represents a particularly interesting example. To people unfamiliar with the accomplishments of turn-of-the-century laryngologist Otto "Tiger" Freer, it can be assumed that the name of the instrument in one's hand is simply named for what it can do, that is, to "free" the nasal mucosa from the bony and cartilaginous septum during the transsphenoidal approach. The technique this master surgeon spent his life and career perfecting is now repeated almost daily by skull base neurosurgeons approaching pathologies from the inferior frontal lobe to the foramen magnum. In reviewing his life and work, the authors of this paper discovered an interesting creative process that led to the design of the eponymous instrument. Additionally, they discovered important advances toward the development of the transnasal approach and in our understanding of the anterior skull base. They present a historical perspective on the life and accomplishments of Dr. Freer and the ubiquitous surgical instrument that he invented and popularized.

Repair of middle fossa cerebrospinal fluid leaks using a novel combination of materials: technical note.

OBJECT: Methods for repairing middle fossa CSF (MFCSF) leaks have varied and yielded mixed results. The objective of this study was to evaluate the safety and durability of the authors' repair technique using a novel combination of 3 synthetic materials. METHODS: The authors performed a retrospective case review of patients treated for CSF leaks between January 2009 and September 2011. Eight patients were found to have undergone middle fossa craniotomies for CSF leaks. Inclusion criteria for the study included age greater than 18 years, neuroimaging-documented temporal bone defect, and symptoms consistent with CSF leaks or gross CSF otorrhea. Seven patients, 3 men and 4 women, met the inclusion criteria, and their charts were reviewed. Hydroxyapatite cement, collagen-based dural substitute matrix, and polyethylene glycol hydrogel sealant were used in all patients for the repair. RESULTS: In all patients the MFCSF leaks were successfully repaired. Initial presenting symptoms included CSF otorrhea in 4 patients (57.1%), hearing loss in 3 (42.9%), and CSF rhinorrhea in 1 (14.3%). The mean follow-up duration was 12 months (range 5-33 months). In 1 patient an epidural hematoma developed at the operative site on postoperative Day 2, and in another patient a superficial wound dehiscence occurred on postoperative Day 48. During the follow-up period, the authors found no evidence of wound infections, neurovascular damage, or CSF leakage requiring reoperation. CONCLUSIONS: The middle fossa approach involving a combination of hydroxyapatite cement, collagen-based dural substitute matrix, and polyethylene glycol hydrogel sealant is a safe, effective method for repairing MFCSF leaks. The combination of synthetic materials provides an alternative to existing materials for skull base surgeons.

Treatment of venous malformations with tumescent-assisted sclero-embolic and ablative lasers (SEALs): Safe and effective long-term outcomes.

BACKGROUND: Perivascular infiltration of tumescent anaesthesia (TA) is an essential element of endovenous thermal ablative procedures employed to treat superficial venous disease. In addition to anaesthesia, TA is administered to achieve vessel wall approximation and to protect surrounding structures from thermal damage. However, its role in the treatment of venous malformations (VMs) has not been established. OBJECTIVES: To assess the safety and efficacy of tumescent-assisted thermal and chemical ablative methods in the treatment of VMs. METHODS: Adult and paediatric patients presenting with VMs were treated using a combination of endovenous laser ablation, foam embolo-sclerotherapy and liquid embolisation using n-BCA. All procedures were ultrasound-guided. Treatment outcomes were assessed in early and late follow-ups. To assess the efficacy of TA in achieving vessel wall approximation, cross-sectional lesional diameters were measured by ultrasound, before and after the administration of TA during endovenous procedures. RESULTS: In a 12 month period, 22 patients recruited in the study presented with 27 VMs which included 23 extra-truncular lesions (16 subcutaneous and seven intramuscular) and four truncular anomalies. On average the subcutaneous lesions measured 5.5 mm (1.9-24.5 mm) in diameter, intramuscular lesions measured 9.2 mm (5.9-15.1 mm) and truncular anomalies measured 4.9 mm (1.2-12 mm) in diameter. Perivascular infiltration of TA resulted in a significant reduction in vessel calibre (90% reduction on average). Intramuscular VMs were less compressible with TA (69.2% reduction) compared to subcutaneous lesions (98% reduction). Truncular anomalies such as the embryonic marginal vein achieved complete approximation (100% reduction). Procedures were safely tolerated with no major complications such as thromboembolism, stroke, nerve damage or tissue necrosis. Most patients had significant clinical as well as ultrasonographic improvement. CONCLUSION: Tumescent-assisted endovenous laser ablation and foam sclerotherapy provides safe and effective outcomes in patients with a variety of VMs.

A novel flow cytometry procoagulant assay for diagnosis of vaccine-induced immune thrombotic thrombocytopenia.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe prothrombotic complication of adenoviral vaccines, including the ChAdOx1 nCoV-19 (Vaxzevria) vaccine. The putative mechanism involves formation of pathological anti-platelet factor 4 (PF4) antibodies that activate platelets via the low-affinity immunoglobulin G receptor FcγRIIa to drive thrombosis and thrombocytopenia. Functional assays are important for VITT diagnosis, as not all detectable anti-PF4 antibodies are pathogenic, and immunoassays have varying sensitivity. Combination of ligand binding of G protein-coupled receptors (protease-activated receptor-1) and immunoreceptor tyrosine-based activation motif-linked receptors (FcγRIIa) synergistically induce procoagulant platelet formation, which supports thrombin generation. Here, we describe a flow cytometry-based procoagulant platelet assay using cell death marker GSAO and P-selectin to diagnose VITT by exposing donor whole blood to patient plasma in the presence of a protease-activated receptor-1 agonist. Consecutive patients triaged for confirmatory functional VITT testing after screening using PF4/heparin ELISA were evaluated. In a development cohort of 47 patients with suspected VITT, plasma from ELISA-positive patients (n = 23), but not healthy donors (n = 32) or individuals exposed to the ChAdOx1 nCov-19 vaccine without VITT (n = 24), significantly increased the procoagulant platelet response. In a validation cohort of 99 VITT patients identified according to clinicopathologic adjudication, procoagulant flow cytometry identified 93% of VITT cases, including ELISA-negative and serotonin release assay-negative patients. The in vitro effect of intravenous immunoglobulin (IVIg) and fondaparinux trended with the clinical response seen in patients. Induction of FcγRIIa-dependent procoagulant response by patient plasma, suppressible by heparin and IVIg, is highly indicative of VITT, resulting in a sensitive and specific assay that has been adopted as part of a national diagnostic algorithm to identify vaccinated patients with platelet-activating antibodies.

Ex Vivo Assessment of Different Oral Anticoagulant Regimens on Pump Thrombosis in a HeartWare Ventricular Assist Device.

BACKGROUND: In light of decreased intracranial hemorrhage with direct oral anticoagulants and concerns about their safety in continuous flow left ventricular assist devices, we conducted an ex vivo study of thrombus formation using multiple anticoagulation agents. METHODS: A continuous flow left ventricular assist device (HeartWare ventricular assist device) hemocompatibility loop was run using human blood under 7 conditions: control (no anticoagulation or antiplatelet); in vitro addition of aspirin; in vitro addition of apixaban at low dose (equivalent 2.5 mg twice daily); addition of apixaban at high dose (equivalent 5 mg twice daily); patients on warfarin; patients on apixaban (5 mg twice daily); and patients on dabigatran (150 mg twice daily). The primary outcome was time to formation of intrapump thrombosis. Secondary outcomes were reduction in clotting times over 1 hour, hemolysis, reduced platelet aggregation, and von Willebrand activity. RESULTS: Twenty-one runs were completed. Times to thrombosis in median (interquartile range) were control, 131 (127-134.5); in vitro aspirin, 124 (114.5-137); and patients on dabigatran, 131 (130.5-135.5) minutes, respectively. Times in patients on warfarin were, 137 (136.5-143.5); in vitro low-dose apixaban, 141 (138.5-142); and patients on apixaban, 140 (138-142.5) minutes, respectively. No thrombus formed in the in vitro high-dose apixaban group. There were no significant differences between the individual groups. When all apixaban groups were compared with nonapixaban groups, the time to thrombosis formation was significantly longer, 143 (137-150) versus 133.5 (128.5-140) minutes, P=0.02. There were similar changes in lactate dehydrogenase levels and other secondary end points. CONCLUSIONS: In an in vitro study of anticoagulation using human blood in a mock loop with a HeartWare HVAD, we demonstrated similar thrombosis times for apixaban and warfarin. Time to clotting was longer in the combined apixaban groups compared with combined other groups, but thrombosis times between individual groups were not significantly different.

Consensus recommendations on flow cytometry for the assessment of inherited and acquired disorders of platelet number and function: Communication from the ISTH SSC Subcommittee on Platelet Physiology.

Flow cytometry is increasingly used in the study of platelets in inherited and acquired disorders of platelet number and function. However, wide variation exists in specific reagents, methods, and equipment used, making interpretation and comparison of results difficult. The goal of the present study was to provide expert consensus guidance on the use of flow cytometry for the evaluation of platelet disorders. A modified RAND/UCLA survey method was used to obtain a consensus among 11 experts from 10 countries across four continents, on the appropriateness of statements relating to clinical utility, pre-analytical variables, instrument and reagent standardization, methods, reporting, and quality control for platelet flow cytometry. Feedback from the initial survey revealed that uncertainty was sometimes due to lack of expertise with a particular test condition rather than unavailable or ambiguous data. To address this, the RAND method was modified to allow experts to self-identify statements for which they could not provide expert input. There was uniform agreement among experts in the areas of instrument and reagent standardization, methods, reporting, and quality control and this agreement is used to suggest best practices in these areas. However, 25.9% and 50% of statements related to pre-analytical variables and clinical utility, respectively, were rated as uncertain. Thus, while citrate is the preferred anticoagulant for many flow cytometric platelet tests, expert opinions differed on the acceptability of other anticoagulants, particularly heparin. Lack of expert consensus on the clinical utility of many flow cytometric platelet tests indicates the need for rigorous multicenter clinical outcome studies.

Sirolimus and propranolol inhibit endothelial proliferation while detergent sclerosants induce endothelial activation, microparticle release and apoptosis in vitro.

OBJECTIVES: To investigate the effects of detergent sclerosants, sodium tetradecyl sulphate and polidocanol, on endothelial cell activation and microparticle release and the effects of detergent sclerosants, sirolimus and propranolol, on apoptosis in vitro. METHODS: Cultured human umbilical vein endothelial cells and murine haemangioendothelioma (EOMA) cell lines were incubated with different concentrations of sodium tetradecyl sulphate and polidocanol, as well as sirolimus and propranolol. Endothelial activation was assessed using flow cytometry for CD62e (E-Selectin), CD54 (ICAM-1), CD105 (endoglin), CD144 (VE-Cadherin), CD146 (MCAM) and the release of endothelial microparticles. Cell proliferation was assessed using [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] and carboxyfluorescein succinimidyl ester assays. Apoptosis was assessed using flow cytometry for lactadherin/propidium iodide staining and for Caspase-3 expression. RESULTS: Sublytic concentrations of sodium tetradecyl sulphate and polidocanol (0.075%-0.3%) increased the expression of the activation markers CD62e and CD54. The expression of CD105 decreased in sclerosant treated cultured human umbilical vein endothelial cells. Both sodium tetradecyl sulphate and polidocanol induced the release of endothelial microparticles. All agents inhibited cell proliferation. Sodium tetradecyl sulphate and polidocanol-induced apoptosis as evidenced by increased phosphatidylserine exposure and caspase-3 expression, whereas sirolimus and propranolol increased caspase-3 expression only. CONCLUSION: Sublytic concentrations of detergent sclerosants induce endothelial activation and the release of endothelial microparticles. All agents were anti-proliferative in EOMA cell lines, with sodium tetradecyl sulphate and polidocanol inducing cellular apoptosis.

The clinical heterogeneity of RUNX1 associated familial platelet disorder with predisposition to myeloid malignancy - A case series and review of the literature.

Germline mutations of runt-related transcription factor-1 (RUNX1) cause familial platelet disorder with predisposition to myeloid malignancy (FPDMM), most commonly associated with thrombocytopenia and propensity to develop myeloid neoplasms. A key clinical question is which patients with a family history of thrombocytopenia should undergo genetic testing for RUNX1 mutations. Typically, molecular diagnosis by genetic sequencing is performed when the clinical phenotype is suggestive of this diagnosis; however, our understanding of the spectrum of associated features suggestive of this diagnosis continues to evolve. Herein, we report a case series of 3 unrelated families with RUNX1-associated FPDMM and clinical phenotypes not typically reported with this condition. These cases expand our understanding of FPDMM and highlight the complexity of transcriptional regulation of hematopoiesis and its potentially diverse phenotypes. We describe our approach to diagnosis and management of these individuals and the importance of long-term surveillance in these cases.

Deep vein sclerosis following sclerotherapy: Ultrasonic and d-dimer criteria.

OBJECTIVES: The aim of sclerotherapy is to induce fibrosclerosis of superficial veins. We postulated that inadvertent entry of sclerosants into deep veins can result in sclerotic occlusion, deep vein sclerosis, a non-thrombotic process distinct from spontaneous deep vein thrombosis. The aim of this study was to assess the role of d-dimer in differentiating between deep vein sclerosis and deep vein thrombosis. METHODS: Proximal trunks of great and small saphenous veins were treated with endovenous laser ablation. Venous tributaries and perforators were treated with foam ultrasound guided sclerotherapy. Ultrasound studies of lower limb deep veins were performed before and one week after the procedures, to detect deep vein occlusions (DVOs). d-dimer levels were measured for DVOs and long-term ultrasound studies monitored the recanalisation rates. RESULTS: In a six-year period, 9143 procedures were performed in 1325 patients for bilateral varicose veins. This included 1124 endovenous laser ablation and 8019 foam ultrasound guided sclerotherapy procedures. A total of 259 DVOs (2.83%) were identified on ultrasound which included 251 deep vein sclerosis (2.74%), seven deep vein thrombosis (0.07%) and one endovenous heat-induced thrombosis (EHIT, 0.08%). d-dimer values <0.5 µg/mL excluded deep vein thrombosis s, 0.5-1.0 µg/mL were more likely to be associated with deep vein sclerosis and >1.0 µg/mL were a more likely to be associated with deep vein thrombosis. Lower sclerosant concentrations and higher foam volumes were associated with increased risk of DVO (p < .0001). No significant relationship was found between DVO and gender or thrombophilia. Deep vein thrombosis and EHIT cases but not deep vein sclerosis patients were anticoagulated. None had thromboembolic complications. Patients were followed up for a median of 299 days (37-1994 days). Recanalisation rates were 71.1% for deep vein sclerosis (92.3% competent) and 71.4% for deep vein thrombosis (60.0% competent). CONCLUSIONS: Deep vein sclerosis is a relatively benign clinical entity distinct from deep vein thrombosis and does not require anticoagulation. Majority of affected veins on long-term follow-up regain patency and competence. d-dimer can be used to assist in differentiating deep vein sclerosis from deep vein thrombosis.

Novel developments in foam sclerotherapy: Focus on Varithena® (polidocanol endovenous microfoam) in the management of varicose veins.

Scope Varithena® is a recently approved commercially available drug/delivery unit that produces foam using 1% polidocanol for the management of varicose veins. The purpose of this review is to examine the benefits of foam sclerotherapy, features of the ideal foam sclerosant and the strengths and limitations of Varithena® in the context of current foam sclerotherapy practices. Method Electronic databases including PubMed, Medline (Ovid) SP as well as trial registries and product information sheets were searched using the keywords, 'Varithena', 'Varisolve', 'polidocanol endovenous microfoam', 'polidocanol' and/or 'foam sclerotherapy/sclerosant'. Articles published prior to 20 September 2016 were identified. Results Foam sclerosants have effectively replaced liquid agents due to their physiochemical properties resulting in better clinical outcomes. Medical practitioners commonly prepare sclerosant foam at the bedside by agitating liquid sclerosant with a gas such as room air, using techniques as described by Tessari or the double syringe method. Such physician-compounded foams are highly operator dependent producing inconsistent foams of different gas/liquid compositions, bubble size, foam behaviour and varied safety profiles. Varithena® overcomes the variability and inconsistencies of physician-compounded foam. However, Varithena® has limited applications due to its fixed sclerosant type and concentration, cost and lack of worldwide availability. Clinical trials of Varithena® have demonstrated efficacy and safety outcomes equivalent or better than physician-compounded foam but only in comparison to placebo alone. Conclusion Varithena® is a promising step towards the creation of an ideal sclerosant foam. Further assessment in independent randomised controlled clinical trials is required to establish the advantages of Varithena® over and above the current best practice physician-compounded foam.