Early Postmarket Results with EmboTrap II Stent Retriever for Mechanical Thrombectomy: A Multicenter Experience.

BACKGROUND AND PURPOSE: EmboTrap II is a novel stent retriever with a dual-layer design and distal mesh designed for acute ischemic stroke emergent large-vessel occlusions. We present the first postmarket prospective multicenter experience with the EmboTrap II stent retriever. MATERIALS AND METHODS: A prospective registry of patients treated with EmboTrap II at 7 centers following FDA approval was maintained with baseline patient characteristics, treatment details, and clinical/radiographic follow-up. RESULTS: Seventy patients were treated with EmboTrap II (mean age, 69.9 years; 48.6% women). Intravenous thrombolysis was given in 34.3%, and emergent large-vessel occlusions were located in the ICA (n = 18), M1 (n = 38), M2 or M3 (n = 13), and basilar artery (n = 1). The 5 × 33 mm device was used in 88% of cases. TICI ≥ 2b recanalization was achieved in 95.7% (82.3% in EmboTrap II-only cases), and first-pass efficacy was achieved in 35.7%. The NIHSS score improved from a preoperative average of 16.3 to 12.1 postprocedure and to 10.5 at discharge. An average of 2.5 [SD, 1.8] passes was recorded per treatment, including non-EmboTrap attempts. Definitive treatment was performed with an alternative device (aspiration or stent retriever) in 9 cases (12.9%). Some hemorrhagic conversion was noted in 22.9% of cases, of which 4.3% were symptomatic. There were no device-related complications. CONCLUSIONS: Initial postmarket results with the EmboTrap II stent retriever are favorable and comparable with those of other commercially available stent retrievers. Compared with EmboTrap II, the first-generation EmboTrap may have a higher first-pass efficacy; however, data are limited by retrospective case analysis, incomplete clinical follow-up, and small sample size, necessitating future trials.

Pipeline Embolization Device in the Treatment of Recurrent Previously Stented Cerebral Aneurysms.

BACKGROUND AND PURPOSE: The use of the Pipeline Embolization Device in the management of recurrent previously stented cerebral aneurysms is controversial. The aim of this study was to evaluate the efficacy and safety of the Pipeline Embolization Device in the treatment of recurrent, previously stented aneurysms. MATERIALS AND METHODS: Twenty-one patients with previously stented recurrent aneurysms who later underwent Pipeline Embolization Device placement (group 1) were retrospectively identified and compared with 63 patients who had treatment with the Pipeline Embolization Device with no prior stent placement (group 2). Occlusion at the latest follow-up angiogram, recurrence and retreatment rates, clinical outcome, complications, and morbidity and mortality observed after treatment with the Pipeline Embolization Device were analyzed. RESULTS: Patient characteristics were similar between the 2 groups. The mean time from stent placement to recurrence was 25 months. Pipeline Embolization Device treatment resulted in complete aneurysm occlusion in 55.6% of patients in group 1 versus 80.4% of patients in group 2 (P = .036). The retreatment rate in group 1 was 11.1% versus 7.1% in group 2 (P = .62). The rate of good clinical outcome at the latest follow-up in group 1 was 81% versus 93.2% in group 2 (P = .1). Complications were observed in 14.3% of patients in group 1 and 9.5% of patients in group 2 (P = .684). CONCLUSIONS: The use of the Pipeline Embolization Device in the management of previously stented aneurysms is less effective than the use of this device in nonstented aneurysms. Prior stent placement can worsen the safety and efficacy profile of this device.

Direct comparison of Neuroform and Enterprise stents in the treatment of wide-necked intracranial aneurysms.

AIM: To compare the complications and outcomes of Neuroform and Enterprise stents in the treatment of unruptured wide-necked aneurysms. MATERIALS AND METHODS: Under the auspices of the institutional review board, a review of a prospectively collected patient log identified 130 patients who underwent elective stent-assisted coil embolization of a wide-necked aneurysm, including 53 patients treated with an Enterprise stent and 77 patients treated with a Neuroform stent. Immediate and long-term clinical and radiographic outcomes were recorded for all patients. All patient data were handled in accordance with Health Insurance Portability and Accountability Act of 1996 (HIPAA) regulations. RESULTS: The technical success rate was 94%. Overall morbidity was 15% with Enterprise stents and 3% with Neuroform stents (p = 0.020). However, the type of stent used was not predictive of clinical outcomes as measured by the modified Rankin scale. In a multivariate analysis, the use of a Neuroform stent was one of the predictors of retreatment (p = 0.034). CONCLUSION: Multivariate analyses identified the use of Neuroform stents as an independent predictor of the need for retreatment and the use of Enterprise stents as an independent predictor of morbidity. However, the type of stent was not predictive of clinical outcome as measured by the modified Rankin scale.

Vision outcomes and major complications after endovascular coil embolization of ophthalmic segment aneurysms.

BACKGROUND AND PURPOSE: As aneurysms arising from the ophthalmic segment of the internal carotid artery increase in size, they can compress the optic nerve, prompting patients to present with visual disturbances. The purpose of this article is to describe the clinical and angiographic results with an emphasis on visual outcomes following the endovascular treatment of ophthalmic segment ICA aneurysms. MATERIALS AND METHODS: The records of 1254 patients who presented for endovascular treatment of a cerebral aneurysm were retrospectively reviewed to identify 65 consecutive patients who underwent coil embolization of an ophthalmic segment ICA aneurysm. The clinical records, treatment reports, and imaging were reviewed with a focus on visual outcomes. RESULTS: Twenty-two of the 65 patients (34%) who presented for treatment of an ophthalmic aneurysm reported a visual disturbance at presentation. Fifteen of the 22 patients (68%) experienced an improvement in their symptoms after treatment. Overall, patients with visual symptoms were significantly more likely to benefit from treatment than to have a decline in vision (P = .03). The overall morbidity was 4%, and mortality was 0%. The retreatment rate was high at 30%, though this was disproportionately weighted by an 86% retreatment rate in patients with ruptured aneurysms. CONCLUSIONS: Patients with visual symptoms attributable to ophthalmic segment ICA aneurysms undergoing endovascular coil embolization were statistically more likely to experience an improvement in their vision than to have worsening or unchanged vision. Coiling was associated with a low morbidity rate, though an elevated retreatment rate.

A single pipeline embolization device is sufficient for treatment of intracranial aneurysms.

BACKGROUND AND PURPOSE: The Pipeline Embolization Device has emerged as an important treatment option for intracranial aneurysms. The number of devices needed to treat an aneurysm is uncertain and is the subject of vigorous debate. The purpose of this study was to compare rates of complications, aneurysm occlusion, and outcome in patients treated with a single-versus-multiple Pipeline Embolization Devices. MATERIAL AND METHODS: One hundred seventy-eight patients were treated with the Pipeline Embolization Device at our institution. Patients were divided into 2 groups: a single-device group (n = 126) and a multiple-device group (n = 52). RESULTS: There was no statistically significant difference between the 2 groups with respect to baseline characteristics except for age and aneurysm size (higher with multiple Pipeline Embolization Devices). Complications occurred more frequently with multiple (15%) versus a single device (5%, P = .03). In multivariate analysis, the use of multiple devices independently predicted complications. A similar proportion of patients achieved adequate aneurysm obliteration at follow-up in the single-device (84%) and the multiple-device groups (87%, P = .8). In multivariate analysis, age and follow-up time predicted obliteration. At follow-up, a significantly higher proportion of patients treated with a single device (97%) achieved a favorable outcome compared with those treated with multiple devices (89%, P = .03). In multivariate analysis, there was a strong trend for the use of a single device to predict favorable outcomes (P = .06). CONCLUSIONS: Treatment with a single Pipeline Embolization Device provides similar occlusion rates with less complications and better overall outcomes. These findings suggest that a single Pipeline Embolization Device is sufficient for treatment of most intracranial aneurysms.

Preoperative embolization of intracranial meningiomas: efficacy, technical considerations, and complications.

BACKGROUND AND PURPOSE: Preoperative embolization for intracranial meningiomas offers potential advantages for safer and more effective surgery. However, this treatment strategy has not been examined in a large comparative series. The purpose of this study was to review our experience using preoperative embolization to understand the efficacy, technical considerations and complications of this technique. MATERIALS AND METHODS: We performed a retrospective review of patients undergoing intracranial meningioma resection at our institution (March 2001 to December 2012). Comparisons were made between embolized and nonembolized patients, including patient and tumor characteristics, embolization method, operative blood loss, complications, and extent of resection. Logistic regression analyses were used to identify factors predictive of operative blood loss and extent of resection. RESULTS: Preoperatively, 224 patients were referred for embolization, of which 177 received embolization. No complications were seen in 97.1%. There were no significant differences in operative duration, extent of resection, or complications. Estimated blood loss was higher in the embolized group (410 versus 315 mL, P=.0074), but history of embolization was not a predictor of blood loss in multivariate analysis. Independent predictors of blood loss included decreasing degree of tumor embolization (P=.037), skull base location (P=.005), and male sex (P=.034). Embolization was not an independent predictor of gross total resection. CONCLUSIONS: Preoperative embolization is a safe option for selected meningiomas. In our series, embolization did not alter the operative duration, complications, or degree of resection, but the degree of embolization was an independent predictor of decreased operative blood loss.

Coiling of large and giant aneurysms: complications and long-term results of 334 cases.

BACKGROUND AND PURPOSE: Large and giant intracranial aneurysms are increasingly treated with endovascular techniques. The goal of this study was to retrospectively analyze the complications and long-term results of coiling in large and giant aneurysms (≥ 10 mm) and identify predictors of outcome. MATERIALS AND METHODS: A total of 334 large or giant aneurysms (≥ 10 mm) were coiled in our institution between 2004 and 2011. Medical charts and imaging studies were reviewed to determine baseline characteristics, procedural complications, and clinical/angiographic outcomes. Aneurysm size was 15 mm on average. Two hundred twenty-five aneurysms were treated with conventional coiling; 88, with stent-assisted coiling; 14, with parent vessel occlusion; and 7, with balloon-assisted coiling. RESULTS: Complications occurred in 10.5% of patients, with 1 death (0.3%). Aneurysm location and ruptured aneurysms predicted complications. Angiographic follow-up was available for 84% of patients at 25.4 months on average. Recanalization and retreatment rates were 39% and 33%, respectively. Larger aneurysm size, increasing follow-up time, conventional coiling, and aneurysm location predicted both recurrence and retreatment. The annual rebleeding rate was 1.9%. Larger aneurysm size, increasing follow-up time, and aneurysm location predicted new or recurrent hemorrhage. Favorable outcomes occurred in 92% of patients. Larger aneurysm size, poor Hunt and Hess grades, and new or recurrent hemorrhage predicted poor outcome. CONCLUSIONS: Coiling of large and giant aneurysms has a reasonable safety profile with good clinical outcomes, but aneurysm reopening remains very common. Stent-assisted coiling has lower recurrence, retreatment, and new or recurrent hemorrhage rates with no additional morbidity compared with conventional coiling. Aneurysm size was a major determinant of recanalization, retreatment, new or recurrent hemorrhage, and poor outcome.

Stent-assisted coiling versus balloon remodeling of wide-neck aneurysms: comparison of angiographic outcomes.

BACKGROUND AND PURPOSE: Stent-assisted coiling and balloon-assisted coiling are 2 well-established techniques for treatment of wide-neck intracranial aneurysms. A direct comparative analysis of angiographic outcomes with the 2 techniques has not been available. We compare the angiographic outcomes of wide-neck aneurysms treated with stent-assisted coiling versus balloon-assisted coiling. MATERIALS AND METHODS: A retrospective review was conducted on 101 consecutive patients treated at our institution, 69 with stent-assisted coiling and 32 with balloon-assisted coiling. Two multivariate logistic regression analyses were performed to determine predictors of aneurysm obliteration and predictors of progressive aneurysm thrombosis at follow-up. RESULTS: The 2 groups were comparable with respect to all baseline characteristics with the exception of a higher proportion of ruptured aneurysms in the balloon-assisted coiling group (65.6%) than in the stent-assisted coiling group (11.5%, P < .001). Procedural complications did not differ between the stent-assisted coiling group (6%) and the balloon-assisted coiling group (9%, P = .5). The rates of complete aneurysm occlusion (Raymond score 1) at the most recent follow-up were significantly higher for the stent-assisted coiling group (75.4%) compared with the balloon-assisted coiling group (50%, P = .01). Progressive occlusion of incompletely coiled aneurysms was noted in 76.6% of aneurysms in the stent-assisted coiling group versus 42.8% in the balloon-assisted coiling group (P = .02). Retreatment rates were significantly lower with stent-assisted coiling (4.3%) versus balloon-assisted coiling (15.6%, P = .05). In multivariate analysis, stented aneurysms independently predicted both complete aneurysm obliteration and progression of occlusion. CONCLUSIONS: Stent-assisted coiling may yield lower rates of retreatment and higher rates of aneurysm obliteration and progression of occlusion at follow-up than balloon-assisted coiling with a similar morbidity rate.

Endovascular treatment of posterior communicating artery aneurysms with oculomotor nerve palsy: clinical outcomes and predictors of nerve recovery.

BACKGROUND AND PURPOSE: ONP is a well-known presentation of PcomA aneurysms. Reports on recovery of ONP with endovascular coiling have been limited to small case series. We assessed the safety and efficacy of endovascular therapy in a series of PcomA aneurysms with ONP. MATERIALS AND METHODS: We reviewed 37 patients with ONP who underwent endovascular treatment in our institution between 2005 and 2011. Published studies were also reviewed to determine the overall rate of ONP recovery with endovascular therapy. RESULTS: Nineteen patients (51.4%) presented with complete ONP, and 18 (48.6%), with partial ONP. Conventional coiling was performed in 31 (83.8%) patients; stent-assisted coiling, in 4 (10.8%); and balloon remodeling, in 2 (5.4%). There was 1 (2.7%) procedural complication (a transient thromboembolic event). Twenty-seven (73%) patients were treated within 3 days from symptom onset. At the last available clinical follow-up, ONP resolution was complete in 14 (37.8%) patients and partial in 19 (51.4%). Only 4 (10.8%) patients showed no signs of nerve recovery. In multivariate analysis, partial ONP and longer follow-up durations were predictors of complete nerve recovery. Treatment timing, type of endovascular embolization, subarachnoid hemorrhage, and initial degree of aneurysm occlusion were not predictors of nerve recovery. Of 169 patients reported in the literature (including ours), ONP resolved completely in 73 (43.2%) patients and partially in 73 (43.2%). CONCLUSIONS: Endovascular therapy is a safe and highly efficient alternative to surgical clipping for PcomA aneurysms with ONP.

Intracranial vertebral artery dissections: evolving perspectives.

Intracranial vertebral artery dissection (VAD) represents the underlying etiology in a significant percentage of posterior circulation ischemic strokes and subarachnoid hemorrhages. These lesions are particularly challenging in their diagnosis, management, and in the prediction of long-term outcome. Advances in the understanding of underlying processes leading to dissection, as well as the evolution of modern imaging techniques are discussed. The data pertaining to medical management of intracranial VADs, with emphasis on anticoagulants and antiplatelet agents, is reviewed. Surgical intervention is discussed, including, the selection of operative candidates, open and endovascular procedures, and potential complications. The evolution of endovascular technology and techniques is highlighted.

Rebleeding after aneurysmal subarachnoid hemorrhage.

Rebleeding after initial aneurysmal subarachnoid hemorrhage (SAH) can have substantial impact on overall patient outcome. While older studies have suggested rebleeding occurs in about 4% of patients during the first day after initial aneurysmal bleed, these studies may have failed to capture very early rebleeds and, consequently, underestimated the impact of rebleeding. An electronic literature search was performed to identify English-language articles published or available for review from February 1975 through October 2010. A total of 43 articles (40 original research and 3 review articles) focused on rebleeding after initial aneurysmal SAH in humans were selected for review. Although most studies supported an incidence of rebleeding ≤4%, studies investigating ultra-early rebleeding reported bleeding within the first 24 h following aneurysmal SAH in as many as 9-17% of patients, with most cases occurring within 6 h of initial hemorrhage. Overall, studies investigating antifibrinolytic therapy to reduce rebleeding have failed to clearly demonstrate overall therapeutic benefit. Short-course antifibrinolytic therapy may have a role prior to initial aneurysm repair, although insufficient data are currently available.

Evaluation of indirect decompression of the lumbar spinal canal following minimally invasive lateral transpsoas interbody fusion: radiographic and outcome analysis.

BACKGROUND: The surgical treatment of lumbar stenosis traditionally includes laminectomy for direct decompression of the spinal canal. Selected patients with spinal stenosis may also require lumbar fusion. Minimally invasive lateral transpsoas interbody fusion has the ability of placing a large interbody cage that can increase disc height and distract the spinal level. The purpose of this study was to examine the concept of indirect decompression of the spinal canal in patients with co-existing lumbar spinal stenosis undergoing lateral transpsoas interbody fusion. MATERIALS AND METHODS: We reviewed 25 consecutive spinal stenosis patients with instability undergoing lateral transpsoas interbody fusion without laminectomy. All patients had relevant symptoms of back pain, leg pain, and/or spinal claudication and met standard criteria for lumbar fusion. Patients were evaluated by outcome analysis scales (VAS scores, Oswestry disability index and treatment intensity scale). Postoperative MRI scans, when available, were evaluated for change in canal dimensions. Statistical significance was assessed by paired t-test, which compares the mean change. There were 25 patients in the study (mean age 61 years). 15 patients had grade I spondylolisthesis. VAS for back pain intensity improved from 7.74 to 2.07 and for frequency from 7.91 to 2.22. VAS for leg pain intensity improved from 7.24 to 1.87 and frequency from 7.41 to 2.35. All improvements were statistically significant (P<0.0001). The Oswestry disability index improved from 55.1 to 16.4 (P<0.0001), and treatment intensity scale improved from 14.6 to 3.7 (P<0.0001). Radiographic evaluation in 20 treated levels (15 patients) found an increase in dural sac dimension of 54% in the anterior-posterior plane and 48% in the medial-lateral plane (P<0.0001). The calculated area of the dural sac increased an average of 143% (range of - 10.4% to + 495%). CONCLUSION: Indirect decompression of spinal stenosis can be achieved with lateral transpsoas interbody fusion with improved clinical outcomes. Pre-op and post-op MRI scans showed a significant increase in dural sac dimensions. The mechanism for this indirect decompression may relate to stretching and unbuckling of the spinal ligaments and a decrease in intervertebral disc bulging. Further studies are needed to determine which stenosis patients undergoing this surgery are most appropriate for indirect decompression alone over laminectomy.

Plasma acrolein levels and their association with delayed ischemic neurological deficits following aneurysmal subarachnoid haemorrhage: a pilot study.

BACKGROUND: The molecular mechanisms of cerebral vasospasm following aneurysmal subarachnoid haemorrhage (aSAH) remain unclear. Acrolein, a reactive metabolite produced in many models of mechanical and ischemic injury, has been shown to cause vasospasm in coronary artery and aorta models. These traits suggest it may play a role in post-aSAH cerebral vasospasm. This pilot study was designed as a preliminary investigation to determine if acrolein levels could be used as a clinical tool to predict the presence of vasospasm. METHODS: Eleven patients with aSAH and Hunt and Hess admission grades of III-V were prospectively enrolled. Patients were stratified according to the presence or absence of vasospasm, defined as a delayed ischaemic neurological deficit in which all other possible causes have been excluded. Soluble acrolein levels were determined at two times points: early (day 1-3 post-SAH) and late (day 8-12 post-SAH) and the change in acrolein levels over this period was computed using a Mann-Whitney test. RESULTS: The change in acrolein levels over this period between the vasospasm and non-vasospasm group trended toward but did not achieve statistical significance (means: 5.68 versus -5.54; medians: 5.27 versus -3.99; range: -8.067 to 22.904 versus -13.83 to 5.199 p=0.13). Five out of six vasospasm patients showed an increase in acrolein levels over the vasospasm period. Three out of four non-vasospasm patients showed a decrease over the vasospasm period. CONCLUSIONS: The results of this pilot study suggest that acrolein levels increase in patients undergoing vasospasm during the vasospasm window. This suggests that acrolein may play a role in the pathways leading up to or following vasospasm. There is a need for larger more definitive studies.

Elevation of monocyte chemoattractant protein-1 in patients experiencing neurocognitive decline following carotid endarterectomy.

BACKGROUND: Previous studies have demonstrated that elevated pre-operative monocyte count is an independent predictor of acute neurocognitive decline following carotid endarterectomy (CEA). Monocyte chemoattractant protein-1 (MCP-1), secreted by human endothelial and monocyte-like cells, is a potent mediator of inflammation and mononuclear cell trafficking. This study examines the relationship between peri-operative serum MCP-1 elevation and post-operative neurocognitive injury following CEA. METHODS: Fifty-two patients undergoing CEA and 67 lumbar laminectomy (LL) controls were administered a battery of five neuropsychological tests pre-operatively and on post-operative day 1 (POD 1). Change in individual test scores from baseline to POD 1 were converted into Z-score and used to develop a point system quantifying the degree of neurocognitive dysfunction relative to change within the LL group. Neurocognitive injury following CEA was defined as a score greater than 2 standard deviations above mean total deficit scores of LL controls. Serum MCP-1 levels were measured pre-operatively and on POD 1 by enzyme-linked immunosorbent assay. FINDINGS: Mean percent MCP-1 elevation was higher for the 13 injured CEA patients (147.7 +/- 32.4%) in our cohort compared to 39 age- and sex-matched uninjured CEA patients (76.0 +/- 16.5%). In unconditional multivariate logistic regression analysis, percent elevation in serum MCP-1 level was associated with neurocognitive injury one day after CEA (OR = 2.19, 95% CI = 1.13-4.26, P = 0.021, for a 100% elevation from pre-operative levels). CONCLUSIONS: Peri-operative elevations in serum MCP-1 levels correlate with acute neurocognitive dysfunction following CEA. These data implicate an inflammatory mechanism in the pathogenesis of Ischaemic neurocognitive decline.

The VWF/ADAMTS13 axis in the antiphospholipid syndrome: ADAMTS13 antibodies and ADAMTS13 dysfunction.

Autoantibodies to ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I motif, member 13) play an important role in the development of microthrombosis in thrombotic thrombocytopenic purpura (TTP). In severe cases of antiphospholipid syndrome (APS), microthrombosis can occur similar to that seen in TTP, suggesting possible mutual pathogenic factors. However, the role of ADAMTS13 in APS is unknown. We hypothesised that aberrations in ADAMTS13 may occur in APS and evaluated ADAMTS13 and von Willebrand factor (VWF) in 68 patients with antiphospholipid antibodies (aPA) including 52 with APS. Thirty-three (49%) had IgG anti-ADAMTS13 with 12 of these patients having reduced ADAMTS13 activity, suggesting neutralising antibodies. Low ADAMTS13 activity (median 34%) was demonstrated in 22/68 (33%), all with normal ADAMTS13 antigen levels consistent with dysfunctional ADAMTS13. Reduced ADAMTS13 activity was not secondary to elevated von Willebrand factor (VWF), or increased VWF secretion (normal VWF propeptide), although a reduced VWF clearance was noted in APS. Analysis found no associations between the ADAMTS13 abnormalities and any aPA profile or thrombotic/obstetric complications, although this study was not adequately powered to address clinical associations. Nevertheless, these findings highlight that ADAMTS13 autoantibodies and ADAMTS13 dysfunction can occur in APS, and although the clinical significance remains undetermined, ADAMTS13 dysfunction may be contributory to thrombogenesis in autoimmune conditions other than TTP.

Prevalence of the ADAMTS-13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is most commonly associated with deficiency or inhibition of von Willebrand factor-cleaving protease (ADAMTS-13) activity. ADAMTS-13 mutations and polymorphisms have been reported in childhood congenital TTP, but their significance in adult onset TTP remains unclear. OBJECTIVES: We sought to identify common ADAMTS-13 mutations in adults with late onset TTP and to investigate whether they may predispose acute clinical episodes of the disorder in adulthood. PATIENTS/METHODS/RESULTS: We detected a missense mutation (C3178T) in exon 24 of ADAMTS-13 in 6/53 (11.3%) adult onset TTP patients, but no normal controls (n = 100). Three of the patients had pregnancy-associated TTP; three had chronic relapsing acute idiopathic TTP. C3178T encodes an arginine to tryptophan (R1060W) substitution in the TSP1-7 domain of ADAMTS-13. In vitro expression of mutant and wild-type ADAMTS-13 demonstrated that R1060W caused severe intracellular retention of ADAMTS-13 (<5% secretion) without affecting its metalloprotease activity. One homozygous and five heterozygous patients were identified. No other causative mutations were discovered, yet all six patients had ADAMTS-13 activity levels <5% at presentation (normal: 66-126%). Antibodies/inhibitors to ADAMTS-13 were detected in three/five heterozygous patients, and all six patients had subnormal antigen levels. Six asymptomatic first-degree relatives, including those of two probands with antibodies, were also heterozygous for C3178T; all but one had subnormal ADAMTS-13 activity. CONCLUSION: The high prevalence of R1060W ADAMTS-13 in adult onset TTP, together with its absence in childhood congenital TTP cases reported elsewhere, suggests it may be a factor in the development of late onset TTP.

Prion protein in patients with renal failure.

We previously found elevated levels of prion protein (PrP(C)) in the blood plasma of 16 patients with renal failure. We studied a further 20 patients with renal failure, and all had a significantly higher PrP(C) concentration than healthy normal subjects (P < 0.0001). Renal dialysis did not remove plasma PrP(C) in these patients. Because dialysis patients receive heparin during dialysis, which could potentially bind to PrP(C), the concentration of PrP(C) was measured in patients receiving heparin for cardiopulmonary bypass and was found to be similar to normal controls. We also studied several other groups with chronic illnesses and found that patients with thrombotic thrombocytopenic purpura and sickle cell anaemia had normal plasma PrP(C) levels, but that those with beta-thalassaemia had slightly elevated levels of plasma PrP(C). This suggests that the observations in renal failure were not just part of a generalized response to chronic illness or acute phase reaction. The mechanism of elevated plasma PrP(C) levels in renal disease is unknown, but this shows that plasma PrP(C) is not a specific marker of neurological disease or Creutzfeldt-Jakob disease.

Thrombotic thrombocytopaenic purpura in HIV-infected patients.

Thrombotic thrombocytopaenic purpura (TTP) results from deficiency of von Willebrand factor-cleaving protease (vWF-cp) activity. Eight HIV-infected patients presented with TTP, representing 12.5% of all TTP treated at this centre. In four patients presentation with TTP revealed underlying HIV infection, the other four patients were previously known to be HIV infected, with plasma exchange and highly active antiretroviral therapy (HAART) all recovered. Normalization of vWF-cp activity was associated with recovery. Relapse occurred in two patients who discontinued HAART against medical advice, suggesting that HIV has a causal role in this condition. Given the clear benefit from HAART in addition to plasma exchange, these data suggest that all patients presenting with TTP should undergo HIV testing.

The expression of prion protein (PrP(C)) in the megakaryocyte lineage.

BACKGROUND: Cellular prion protein (PrP(C)) is a naturally occurring protein in normal individuals which adopts an abnormal conformation, termed scrapie prion protein (PrP(Sc)) that is associated with disease. There is great concern that clinically asymptomatic variant Creutzfeldt-Jacob disease (vCJD) may transmit PrP(Sc) in blood transfusion products. PrP(C) is widely expressed and has been found in human blood. The majority of cellular borne PrP(C) is associated with platelets (84%). Although PrP(C) mRNA has been demonstrated in platelets, the quantity is unknown and may not reflect the total PrP(C) present. OBJECTIVE: To investigate the expression of PrP(C) in the megakaryocyte lineage. METHODS: The expression of PrP(C) was studied in CD34+ cells, cultured megakaryocytes and platelets using electron microscopy, flow cytometry, semi-quantitative RT-PCR and immunofluorescence confocal microscopy. RESULTS AND CONCLUSIONS: The expression of PrP(C) appeared to increase with differentiation and polyploidization in the megakaryocyte lineage. PrP(C) was located within platelet alpha-granules and its source is likely to be from megakaryocyte precursors. If PrP(Sc) has a similar distribution, these results have implications for the selection of blood donors and preparation of cell-depleted blood products.