Comprehensive Analyses of Coagulation Parameters in Patients with Vascular Anomalies.

BACKGROUND: Vascular anomalies comprise a diverse group of rare diseases with altered blood flow and are often associated with coagulation disorders. The most common example is a localized intravascular coagulopathy in venous malformations leading to elevated D-dimers. In severe cases, this may progress to a disseminated intravascular coagulopathy with subsequent consumption of fibrinogen and thrombocytes predisposing to serious bleeding. A separate coagulopathy is the Kasabach-Merritt phenomenon in kaposiform hemangioendothelioma characterized by platelet trapping leading to thrombocytopenia and eventually consumptive coagulopathy. Our previous work showed impaired von Willebrand factor and platelet aggregometry due to abnormal blood flow, i.e., in ventricular assist devices or extracorporeal membrane oxygenation. With altered blood flow also present in vascular anomalies, we hypothesized that, in particular, the von Willebrand factor parameters and the platelet function may be similarly impacted. METHODS: We prospectively recruited 73 patients with different vascular anomaly entities and analyzed their coagulation parameters. RESULTS: Acquired von Willebrand syndrome was observed in both of our patients with Kasabach-Merritt phenomenon. In six out of nine patients with complex lymphatic anomalies, both the vWF antigen and activity were upregulated. Platelet aggregometry was impaired in both patients with Kasabach-Merritt phenomenon and in seven out of eight patients with an arteriovenous malformation. CONCLUSIONS: The analysis of coagulation parameters in our patients with vascular anomalies advanced our understanding of the underlying pathophysiologies of the observed coagulopathies. This may lead to new treatment options for the, in part, life-threatening bleeding risks in these patients in the future.

¿Cómo tratamos el hemangioendotelioma kaposiforme? / How do we treat Kaposiform Haemangioendothelioma?

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Re-endothelialisation after Synergy stent and Absorb bioresorbable vascular scaffold implantation in acute myocardial infarction: COVER-AMI study.

BACKGROUND/AIMS: Drug eluting stent (DES) decrease the risk of restenosis by reducing the neointimal response. However, DES may impair strut coverage, and this has been associated with late stent/scaffold thrombosis. Bioresorbable vascular scaffold (BVS) may overcome the risk of stent/scaffold thrombosis when completely resorbed. The purpose of this randomised trial was to compare the arterial healing response in the short term, as a surrogate for safety and efficacy, between the metallic everolimus-eluting stent (Synergy; Boston Scientific, Marlborough, MA, USA) and the everolimus BVS (Absorb; Abbott Vascular, Santa Clara, CA, USA) in the particular setting of acute myocardial infarction (AMI). This pilot study sought to compare the neointimal response of metallic everolimus DES (Synergy) with polymeric everolimus BVS (Absorb) by optical coherence tomography (OCT) 3 months after an AMI. METHODS: COVER-AMI was a single-centre, single-blind, non-inferiority, randomised controlled trial. Patients with ST segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention were randomly allocated (1:1) to treatment with the Synergy DES or Absorb BVS. The primary endpoint was the 3-month neointimal response assessed as the percentage of uncovered struts, neointimal thickness, in-stent/scaffold area obstruction, and pattern of neointima. The main secondary endpoint included the device-oriented composite endpoint according to the Academic Research Consortium definition. RESULTS: Twenty patients without clinical and/or angiographic complications (Synergy (n = 10) or BVS (n = 10); mean age 59.0 years; 20% female) were enrolled in our centre. The stent diameter was higher in the Synergy group (3.7 ± 0.4 mm vs 3.4 ± 0.4 mm in the BVS group, p = 0.01). At 3 months, no significant differences in angiographic lumen loss were observed between the everolimus DES and everolimus BVS (0.04 mm (IQR 0.00-0.07) vs 0.11 mm (IQR 0.04-0.31), p = 0.165). OCT analysis of 420 cross-sections showed that the total neointimal area and in-stent obstruction were lower in the Synergy group, while OCT analysis at the strut level (n = 3942 struts) showed that the rate of uncovered struts was lower in the BVS group. CONCLUSIONS: Stenting of culprit lesions in the setting of STEMI resulted in a nearly complete arterial healing for both the Synergy and the BVS devices. Lower neointimal thickness and in-stent obstruction but a higher rate of uncovered struts were observed in the Synergy group. These findings provide the basis for further exploration in clinically oriented outcome trials.

Resolution of reactive angioendotheliomatosis in an arteriovenous fistula with innominate vein angioplasty.

INTRODUCTION: Arteriovenous fistulae (AVF)-associated reactive angioendotheliomatosis (RAE) is a very rare entity (three previously reported cases in the literature) that can manifest as extremity wounds. RAE's etiopathology is unknown. CASE DESCRIPTION: We report a case of severe limb-threatening upper extremity wound with pathology-proven RAE. This lesion was previously refractory to standard wound care. There was no evidence of limb ischemia or steal syndrome, previously deemed to be the underlying cause of AVF-associated RAE in other reports. CONCLUSIONS: Successful endovascular treatment of an ipsilateral innominate vein stenosis led to reduction of venous hypertension, resolution of associated arm edema, and subsequent wound healing. We therefore propose that venous engorgement and hypertension from central venous stenosis is the likely underlying cause for AVF-associated RAE. If this rare entity is encountered in the setting of AVF, there is utility in treating the wound as a sentinel lesion and venography should be conducted to rule out central venous pathology. Vascular intervention complements aggressive local wound management and biopsy is requisite for prompt diagnosis.

Restricted Range of Motion and a Cold Upper Extremity in a Two-Year-Old Boy: Kaposiform Hemangioendothelioma of the Bone and the Brachial Plexus: A Case Report.

CASE: We report a case of kaposiform hemangioendothelioma (KHE) of the scapula in a 2-year-old boy with motor and sensory abnormalities of the left upper extremity, suggesting brachial plexus involvement. The locally invasive nature prevented resection; sirolimus therapy resulted in improvement of the motor and sensory impairment, as well as decreased tumor size on imaging. CONCLUSION: Osseous infiltration of KHE is known to occur, but its primary presentation in bone without skin involvement is rare and diagnostically challenging. Awareness of rare presentations of KHE, along with accurate histopathologic interpretation, is important to achieve a diagnosis and to differentiate KHE from more common vascular lesions (e.g., infantile hemangioma). Sirolimus therapy is emerging as a promising treatment for unresectable KHE.

Heat stress prevents lipopolysaccharide-induced apoptosis in pulmonary microvascular endothelial cells by blocking calpain/p38 MAPK signalling.

Pulmonary microvascular endothelial cells (PMECs) injury including apoptosis plays an important role in the pathogenesis of acute lung injury during sepsis. Our recent study has demonstrated that calpain activation contributes to apoptosis in PMECs under septic conditions. This study investigated how calpain activation mediated apoptosis and whether heat stress regulated calpain activation in lipopolysaccharides (LPS)-stimulated PMECs. In cultured mouse primary PMECs, incubation with LPS (1 µg/ml, 24 h) increased active caspase-3 fragments and DNA fragmentation, indicative of apoptosis. These effects of LPS were abrogated by pre-treatment with heat stress (43 °C for 2 h). LPS also induced calpain activation and increased phosphorylation of p38 MAPK. Inhibition of calpain and p38 MAPK prevented apoptosis induced by LPS. Furthermore, inhibition of calpain blocked p38 MAPK phosphorylation in LPS-stimulated PMECs. Notably, heat stress decreased the protein levels of calpain-1/2 and calpain activities, and blocked p38 MAPK phosphorylation in response to LPS. Additionally, forced up-regulation of calpain-1 or calpain-2 sufficiently induced p38 MAPK phosphorylation and apoptosis in PMECs, both of which were inhibited by heat stress. In conclusion, heat stress prevents LPS-induced apoptosis in PMECs. This effect of heat stress is associated with down-regulation of calpain expression and activation, and subsequent blockage of p38 MAPK activation in response to LPS. Thus, blocking calpain/p38 MAPK pathway may be a novel mechanism underlying heat stress-mediated inhibition of apoptosis in LPS-stimulated endothelial cells.

Kasabach-Merritt phenomenon.

The objective of this article is to provide a comprehensive overview of the Kasabach-Merritt Phenomenon. The clinical presentation, laboratory findings, vascular pathology, and pathophysiology are discussed.

High-intensity interval training may reduce in-stent restenosis following percutaneous coronary intervention with stent implantation A randomized controlled trial evaluating the relationship to endothelial function and inflammation.

BACKGROUND: High-intensity interval training has been shown to be superior to moderate continuous exercise training in improving exercise capacity and endothelial function in patients with coronary artery disease. The objective of this study was to evaluate this training model on in-stent restenosis following percutaneous coronary intervention for stable or unstable angina. METHODS AND RESULTS: We prospectively randomized 40 patients after percutaneous coronary intervention with implantation of a bare metal stent (n = 30) or drug eluting stent (n = 32) to a 6-month supervised high-intensity interval exercise training program (n = 20) or to a control group (n = 20). At six months, restenosis, measured as in-segment late luminal loss of the stented coronary area, was smaller in the training group 0.10 (0.52) mm compared to the control group 0.39 (0.38) mm (P = .01). Reduction of late luminal loss in the training group was consistent with both stent types. Peak oxygen uptake increased in the training and control group by 16.8% and 7.8%, respectively (P < .01). Flow-mediated dilation improved 5.2% (7.6) in the training group and decreased -0.1% (8.1) in the control group (P = .01). Levels of high-sensitivity C-reactive protein decreased by -0.4 (1.1) mg/L in the training group and increased by 0.1 (1.2) mg/L in the control group (P = .03 for trend). CONCLUSIONS: Regular high-intensity interval exercise training was associated with a significant reduction in late luminal loss in the stented coronary segment. This effect was associated with increased aerobic capacity, improved endothelium function, and attenuated inflammation.

Mediastinal composite hemangioendothelioma. A rare tumor at an unusual location.

Composite hemangioendothelioma is a rare vascular tumor; only 12 cases have been previously described in the extremities, tongue and axilla. We report the first case of composite hemangioendothelioma of the mediastinum in a 50-year-old woman. She was admitted to our hospital with dyspnea and cough lasting for two months. Her chest roentgenogram and computed tomography showed a 6 x 4 x 3 cm mass in the middle mediastinum compressing the trachea. She underwent total sternotomy and resection of the mass. Microscopically the most important feature at low power was the variability in the histological pattern. This case is presented not only for the rarity of the tumor type but also for its unusual location.

Refractory kaposiform hemangioendothelioma that expressed vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3: a case report.

This report describes the case of a 10-month-old boy who was diagnosed to have kaposiform hemangioendothelioma (KHE) with Kasabach-Merritt syndrome (KMS), which is a rare pediatric vascular tumor with a high mortality rate. Although both KHE with KMS were resistant to various therapies, such as oral prednisolone, sclerotherapy, and chemotherapy, repeated radiation therapy with methylprednisolone pulse therapy did reduce the volume of KHE and improved the symptoms of KMS. Unfortunately, a regrowth of KHE with KMS was observed 4 months after the cessation of treatment and the patient thereafter died from an intracranial hemorrhage and Pneumocystis carinii pneumonia, which is a complication related to repetitive radiation and steroid therapy. A histopathologic examination of autopsy specimens confirmed a diagnosis of KHE and immunohistologic staining was positive for vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3. These findings may provide the rationale to further investigate the role of VEGFRs in the pathogenesis of KHE and also to elucidate its prognostic value, along with the application of inhibitors for VEGFRs for the treatment of refractory KHE.

Pentoxifylline and its major oxidative metabolites exhibit different pharmacological properties.

Previous investigations indicate that some of the metabolites of the hemorheological agent pentoxifylline (PTX), namely 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (M1), 1-(4-carboxybutyl)-3,7-dimethylxanthine (M4) and 1-(3-carboxypropyl)-3,7-dimethylxanthine (M5), concur to some of the biological effects of the drug. However, information on the bioactivity of the major circulating oxidative metabolites of PTX (M4 and M5) is scanty. Here, we compared the effects of M4 and M5 with that of PTX and its major reductive metabolite, M1, on TNF-alpha production and cytotoxicity, endothelial cell proliferation and on the ATPase activity related to some ATP-binding cassette (ABC) transporters. Unlike PTX and M1, M4 and M5 poorly inhibited lipopolysaccaride-stimulated tumor necrosis factor-alpha (TNF-alpha) release by RAW 264.7 murine macrophages, and did not affect at all cell proliferation and upregulation of TNF-alpha-induced vascular cell adhesion molecule-1 (VCAM-1) in H5V endothelioma cells. By contrast, M4 and M5 were more effective than PTX and M1 in protecting WC/1 murine fibrosarcoma cells from TNF-alpha cytotoxicity. Moreover, results from ATP hydrolase assays indicated that neither PTX nor its tested metabolites interacted significantly with the human multidrug resistance transporters p-glycoprotein/multidrug resistance 1 (MDR1), multidrug resistance-related protein 1 (MRP1), and breast cancer resistance protein (BCRP). Based on these results and literature data, M5, retaining some of the PTX effects but lacking in significant inhibition of TNF-alpha production, may be a promising candidate drug for certain pathologic conditions.

Hemangioendothelioma of the spinal cord with intramedullary extension.

OBJECTIVE: Hemangioendotheliomas (HE) are vascular neoplasms that rarely involve the neuraxis. We report a rare case in the literature of intradural HE of the spinal cord with intramedullary extension. CLINICAL PRESENTATION AND INTERVENTIONS: A 41-year-old gentleman presented with low back pain, numbness and urinary retention. Imaging revealed a spinal tumor causing complete blockage at the level of T12. The tumor was resected and postoperative radiotherapy was delivered for residual disease. No disease was seen on MRI after 48 months of clinical and radiological follow-up. CONCLUSION: Complete excision of HE is the treatment of choice. Radiotherapy may play a role in the management of this lesion.