Early Venous Thrombosis Research Articles

Establishment of a hybrid model of atherosclerosis and acute colitis in ApoE-/- mice.

Inflammatory bowel disease (IBD) and atherosclerosis (AS) are both common chronic inflammatory diseases with similar pathophysiological mechanisms. Some studies have shown that IBD patients are at increased risk for early atherosclerosis, myocardial infarction and venous thrombosis. Here we set up a hybrid mouse model associated with atherosclerosis and acute colitis in order to investigate the interplay of the two diseases. We fed ApoE-/- mice with high fat diet to establish atherosclerosis model, and used animal ultrasound machine to detect the artery of mice noninvasively. Then a new hybrid model of atherosclerosis and acute colitis was prepared by drinking water for 7 days. At the end of the experiment, the hybrid model mice showed typically pathological and intuitionistic changes of atherosclerosis and acute colitis. We found the shortened colon length, high histopathological scores of the colon with mucosal erosion and necrosis, hyperlipidemia, a plaque-covered mouse aorta and plaque with foam cells and lipid deposition in the hybrid model group, which proved that the hybrid model was successfully established. At the same time, ultrasonic detection showed that the end-diastolic blood flow velocity and the relative dilation value were decreased, while systolic time / diastolic time, the wall thickness, systolic diameters as well as diastolic diameters were gradually increased, and statistical significance appeared as early as 8 weeks. We clearly described the process of establishing a hybrid model of atherosclerosis and acute colitis, which might provide a repeatable platform for the interaction mechanism exploring and drug screening of atherosclerosis and inflammatory bowel disease in preclinical study.

Management of Open Tile C Pelvic Fractures and Their Outcomes: A Retrospective Study of 30 Cases.

BackgroundOpen Tile C pelvic fractures are particularly severe. However, reports on their management and outcomes are relatively rare. This study analyzed the demographic and clinical characteristics of patients with open Tile C pelvic fractures and describes our management and outcomes of these injuries.MethodsThis retrospective review included all patients with open Tile C pelvic fractures treated in our department between January 2014 and June 2021. Data on patient demographics, characteristics of the injuries, surgical management, and outcomes were analyzed.ResultsThirty patients with a mean age of 34.0 years met the diagnostic criteria. The average Injury Severity Score was 40.3. According to the Tile fracture classification, 6 patients sustained type C1.1, 12 sustained type C1.2, 3 sustained type C1.3, 5 sustained C2 and 4 sustained type C3. Most patients had soft tissue injuries in multiple zones. All patients sustained associated injuries. Management consisted of bed rest in 8 cases, external fixation as the final strategy in 14, conversion from external fixation to internal fixation in 3, open reduction with internal fixation in 5, and amputation in 6. The average amount of packed red blood cells transfused was 33.3 units, the average intensive care unit stay was 11.3 days, the mean number of operations required was 6.2, and the mean length of hospital stay was 81.8 days. The main complications were early soft tissue infections and venous thrombosis. One patient died of sepsis and multi-organ failure. Soft tissue injuries in multiple zones increased utilization of hospital resources whereas anorectal injuries did not. Vascular damage accompanying truck crush injuries had a high amputation rate.ConclusionOpen Tile C pelvic fractures require multidisciplinary diagnosis and management and consume considerable hospital resources. More emphasis needs to be placed on this complex injury.

Distal facial vein catheterization for prevention and management of thrombosis in vascularized lymph node transfers.

This study investigated the outcomes of the distal facial vein catheterization (DFVC) to manage venous thrombosis in vascularized submental lymph nodes (VSLN) flap transplantations. Between March 2017 and December 2020, patients who underwent VSLN flaps were divided into Group I: combined delayed primary retention sutures (DPRS) with DFVC, and Group II: DPRSalone. Primary outcomes were early (within 72 h) and late venous thrombosis. Secondary outcomes included other nonvascular complications and mechanical factors of the thrombosis. A total of 105 patients who underwent 106 VSLN flaps, including 37 and 69 flaps in Groups I and II, respectively, were included. There were no statistically significant differences in age, body mass index, Taiwan lymphoscintigraphy staging, and surgical factors between the two groups (all p > 0.05). Early venous thrombosis requiring re-exploration developed in one (2.7%) and three (4.3%) flaps in Groups I and II, respectively (p = 0.20). One flap (2.7%) and eight (11.5%) flaps developed late venous thrombosis in Groups I and II, respectively (p < 0.01). There was no statistically significant difference in total complication rates between both groups (p = 0.9). VSLN flap transplantation had a significantly higher risk of late venous thrombosis. DFVC significantly decreased the late venous thrombosis.

High penetrance of inferior vena cava system atresia in severe thrombophilia caused by homozygous antithrombin Budapest 3 variant: Description of a new syndrome

Atresia of inferior vena cava (IVC) is a rare congenital malformation associated with high risk of venous thrombosis that still has unknown etiology, although intrauterine IVC thrombosis has been suggested to be involved. The identification of IVC atresia in a case with early idiopathic venous thrombosis and antithrombin deficiency caused by the homozygous SERPINC1 c.391C > T variant (p.Leu131Phe; antithrombin Budapest 3) encouraged us to evaluate the role of this severe thrombophilia in this vascular abnormality. We have done a cross-sectional study in previously identified cohorts of patients homozygous for the Budapest 3 variant (N=61) selected from 1118 patients with congenital antithrombin deficiency identified in two different populations: Spain (N=692) and Hungary (N=426). Image analysis included computed tomography and phlebography. Atresia of the IVC system was observed in 17/24 cases (70.8%, 95% confidence interval [CI]: 48.9%-87.3%) homozygous for antithrombin Budapest 3 with available computed tomography (5/8 and 12/16 in the Spanish and Hungarian cohorts, respectively), 16 had an absence of infrarenal IVC and one had atresia of the left common iliac vein. All cases with vascular defects had compensatory mechanisms, azygos-hemiazygos continuation or double IVC, and seven also had other congenital anomalies. Short tandem repeat analysis supported the specific association of the IVC system atresia with SERPINC1. We show the first evidence of the association of a severe thrombophilia with IVC system atresia, supporting the possibility that a thrombosis in the developing fetal vessels is the reason for this anomaly. Our hypothesis-generating results encourage further studies to investigate severe thrombophilic states in patients with atresia of IVC.

Post-operative heparin reduces early venous thrombotic complications after orthotopic paediatric liver transplantation.

Despite significant improvements in surgical techniques and medical care, thrombotic complications still represent the primary cause of early graft failure and re-transplantation following paediatric liver transplantation. There is still no standardized approach for thrombosis prevention. The study aimed to evaluate the effectiveness of early intravenous unfractionated heparin started 12 hours postoperatively at 10 UI/kg per hour and used a retrospective "before and after" design to compare the incidence of early thrombotic complications prior to (2002-2010) and after (2011-2016) the introduction of heparin in our institute. From 2002 to 2016, 479 paediatric patients received liver transplantation in our institution with an overall survival rate over one year of 0.91 (95% CI: 0.87-0.94). Of 365 eligible patients, 244 did not receive heparin while 121 did receive heparin. We reported a lower incidence of venous thrombosis (VT) in the group treated with heparin: 2.5% (3/121) vs 7.9% (19/244) (p=0.038). All clinical and laboratory variables considered potential risk factors for VT were studied. By multivariate stepwise Cox proportional hazards models, heparin prophylaxis resulted significantly associated to a reduction in VT (HR=0.29 [95% CI: 0.08-0.97], p=0.045), while age <1 year was found to be an independent risk factor for VT (HR=2.62 [95% CI: 1.11-6.21]; p=0.028). Early postoperative heparin could be considered a valid and safe strategy to prevent early VT after paediatric liver transplantation without a concomitant increase in bleeding. A future randomised control trial is mandatory in order to strengthen this conclusion.

Early graft losses in paired kidney exchange: Experience from 10years of the National Kidney Registry.

Cooperative kidney paired donation (KPD) networks account for an increasing proportion of all living donor kidney transplants in the United States. There are sparse data on the rate of primary nonfunction (PNF) losses and their consequences within KPD networks. We studied National Kidney Registry (NKR) transplants (February 14, 2009 to December 31, 2017) and quantified PNF, graft loss within 30days of transplantation, and graft losses in the first-year posttransplant and assessed potential risk factors. Of 2364 transplants, there were 38 grafts (1.6%) lost within the first year, 13 (0.5%) with PNF. When compared to functioning grafts, there were no clinically significant differences in blood type compatibility, degree of HLA mismatch, number of veins/arteries, cold ischemia, and travel times. Of 13 PNF cases, 2 were due to early venous thrombosis, 2 to arterial thrombosis, and 2 to failure of desensitization and development of antibody-mediated rejection (AMR). Given the low rate of PNF, the NKR created a policy to allocate chain-end kidneys to recipients with PNF following event review and attributable to surgical issues of donor nephrectomy. It is expected that demonstration of low incidence of poor early graft outcomes and the presence of a "safety net" would further encourage program participation in national KPD.

Analysis of Central Venous Access Device (CVAD) Complications in the Setting of Concomitant Surgical Procedures: Is Early Venous Thrombosis a Risk Factor for CVAD Infection?

Analysis of Central Venous Access Device (CVAD) Complications in the Setting of Concomitant Surgical Procedures: Is Early Venous Thrombosis a Risk Factor for CVAD Infection?

Limited orthopaedic surgery combined with external fixation for the treatment of lower extremity sequelae of middle and old aged post-poliomyelitis

To summarize the effectiveness of limited orthopedic surgery combined with external fixation for the treatment of lower extremity sequelae of middle and old aged post-poliomyelitis, and then to explore the strategy of surgical correction and functional reconstruction method. From the database of 23 310 cases of poliomyelitis sequelae treated by QIN Sihe Orthopaedic Surgical team between September 1982 and December 2017, 629 patients over 41 years old were retrieved and the epidemiological characteristics of the patients were analyzed. Between March 2011 and June 2015, 57 patients with poliomyelitis sequelae treated with limited operation and external fixation were followed up 2-6 years, and the history of poliomyelitis sequelae was 41-67 years (mean, 47.1 years). Preoperative histopathological gait included 29 cases of quadriceps gait, 17 cases of walking with crutch, and 11 cases of claudication only. The operative methods included Achilles tendon lengthening in 52 cases, supracondylar osteotomy in 39 cases, knee flexion release in 36 cases, calcaneal arthrodesis in 27 cases, flexion and hip arthrodesis in 21 cases, tibia and fibula osteotomy in 19 cases, triple arthrodesis in 11 cases, and tendon transposition in 1 case. After operation, 18 cases were treated with combined external fixator and 39 cases with Ilizarov ring external fixator. Of the 629 cases, 481 cases were less than 50 years old (76.47%), accounting for 144 cases between 51 and 65 years old (22.89%). Among them, 495 cases (78.70%) were diagnosed after 2003. Of the 57 patients obtained complete follow-up information, 7 had slight infection of needle path during traction orthopaedics, 2 had early postoperative venous thrombosis of lower extremities, and 2 had incomplete paralysis of the common peroneal nerve. There was no complications such as skin incision infection, vascular injury, and bone nonunion. According to the evaluation standard of postoperative efficacy standard in correction of lower extremity deformities, the results were excellent in 23 cases, good in 20 cases, fair in 12 cases, and poor in 2 cases, with an excellent and good rate of 75.44%. The 2 patients with poor effectiveness were reoperated to improve their function. Limited orthopedic surgery combined with external fixation for the treatment of lower extremity sequelae of middle and old aged post-poliomyelitis can effectively correct deformities of lower limbs, improve function, delay the disability aggravated by decay, and avoid serious complications.

Association between modified wells score and D-dimer in malignant lymphoma patients.

Background: Cancer patients have a high risk of new or recurrent venous thromboembolism. Thrombosis decrease 1 year life expectancy of malignant lymphoma patients. In the last 10 years, it has been continuosly developed a method to detect early venous thrombosis by combining Modified Wells (MW), D-dimer and Doppler ultrasonography level but only 25% are detected early. Objective: We analyzed the association between MW score and D-dimer level. Method: It is an analytic observational study of LNH and LH patients based on clinical and histopathological diagnosis who had never received chemotherapy. The subjects were 35 patients with malignant lymphoma consisting of 30 LNH patients and 5 LH patients. D-dimer was measured using immunochromatography method. Result: There was a positive linear relationship between MW score and D-dimer level with p=0.001 and r=0.462. However, there was no association in LH patients (p=0.215). Conclusion: There was a moderate positive correlation between MW scores and D-dimer levels in naive LNH patients.

Abstract 530: In vivo DVT Inflammation Presages Vein Wall Injury, and is Ameliorated by Statin Therapy

Objective: Inflammation mediates early venous thrombosis (VT) resolution and can induce vein wall scarring (VWS), a key driver of the morbid post-thrombotic syndrome (PTS). Statins exhibit anti-inflammatory properties, and may positively impact VWS after VT. However, whether early inflammation contributes to this process and can be detected is not known. In this study, we hypothesized that early VT inflammation detected by 18F-fludeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) could predict subsequent VWS and that both VT inflammation and VWS would be attenuated by statin therapy. Methods: Stasis VT was induced by complete ligation in male C57BL/6J mice (n=55) in either the infrarenal inferior vena cava (IVC, n=42) or right jugular vein (n=13). IVC VT mice were randomized to statin or control groups. Statin (rosuvastatin 5mg/kg) was given by oral gavage starting one day prior to VT induction; control mice received PBS. All mice underwent survival FDG-PET/CT venography imaging on day 2. FDG-PET inflammation signals (standard uptake value (SUV), SUVmax, target-to-background ratios (TBR)) were measured. Picrosirius red staining of day 14 VT sections measured vein wall collagen/thickness. Ex vivo VT tissue gamma counting of a subgroup was performed at day 2. Whole-thrombus protein/mRNA and VT tissue sections assessed neutrophil content. Results: FDG-PET/CT at day 2 revealed increased FDG uptake in jugular VT over the contralateral sham surgery vein (p&lt;0.001). Statin-treated mice showed a decrease in FDG-PET SUV, SUVmax and TBR (p&lt;0.05 for all). Whole-thrombus analyses and tissue section immunostaining showed reduced thrombus neutrophil content at day 2, without reducing GLUT1 or MPO expression (p&gt;0.05). At day 14, statin therapy significantly reduced VWS (p=0.02). In mice undergoing survival imaging, the day 2 FDG-PET VT inflammation signal correlated significantly with the magnitude of day 14 VWS (IVC VT r=0.74, p&lt;0.001) and jugular models of VT (r=0.62, p=0.02). Conclusions: Quantitative FDG inflammation imaging demonstrates that early VT inflammation presages subsequent VWS, and is ameliorated by prophylactic statin therapy. The overall findings support the concept that statins and could reduce VWS and PTS.

Transient desialylation in combination with a novel antithrombin deficiency causing a severe and recurrent thrombosis despite anticoagulation therapy

An in-depth focused study of specific cases of patients with recurrent thrombosis may help to identify novel circumstances, genetic and acquired factors contributing to the development of this disorder. The aim of this study was to carry out a detailed and sequential analysis of samples from a patient suffering from early and recurrent venous and arterial thrombosis. We performed thrombophilic tests, biochemical, functional, genetic and glycomic analysis of antithrombin and other plasma proteins. The patient carried a new type I antithrombin mutation (p.Ile218del), whose structural relevance was verified in a recombinant model. Experiments with N-glycosidase F and neuraminidase suggested a nearly full desialylation of plasma proteins, which was confirmed by mass spectrometry analysis of transferrin glycoforms. However, partial desialylation and normal patterns were detected in samples collected at other time-points. Desialylation was noticeable after arterial events and was associated with low antithrombin activity, reduced platelet count and glomerular filtration rate. This is the first description of a global and transient desialylation of plasma proteins associated with thrombosis. The decrease in the strong electronegative charge of terminal glycans may modulate hemostatic protein-protein interactions, which in combination with a strong prothrombotic situation, such as antithrombin deficiency, could increase the risk of thrombosis.

Endotoxaemia-augmented murine venous thrombosis is dependent on TLR-4 and ICAM-1, and potentiated by neutropenia.

Venous thromboembolism is a major cause of death during and immediately post-sepsis. Venous thrombosis (VT) is mediated by cell adhesion molecules and leukocytes, including neutrophil extracellular traps (NETs). Sepsis, or experimentally, endotoxaemia, shares similar characteristics and is modulated via toll like receptor 4 (TLR4). This study was undertaken to determine if endotoxaemia potentiates early stasis thrombogenesis, and secondarily to determine the role of VT TLR4, ICAM-1 and neutrophils (PMNs). Wild-type (WT), ICAM-1-/- and TLR4-/- mice underwent treatment with saline or LPS (10 mg/kg i. p.) alone, or followed by inferior vena cava (IVC) ligation to generate stasis VT. In vivo microscopy of leukocyte trafficking was performed in non-thrombosed mice, and tissue and plasma were harvested during early VT formation. Pre-thrombosis, circulating ICAM-1 was elevated and increased leukocyte adhesion and rolling occurred on the IVC of LPS-treated mice. Post-thrombosis, endotoxaemic mice formed larger, platelet-poor thrombi. Endotoxaemic TLR4-/- mice did not have an augmented thrombotic response and exhibited significantly decreased circulating ICAM-1 compared to endotoxaemic WT controls. Endotoxaemic ICAM-1-/- mice had significantly smaller thrombi compared to controls. Hypothesising that PMNs localised to the inflamed endothelium were promoting thrombosis, PMN depletion using anti-Ly6G antibody was performed. Paradoxically, VT formed without PMNs was amplified, potentially related to endotoxaemia induced elevation of PAI-1 and circulating FXIII, and decreased uPA. Endotoxaemia enhanced early VT occurs in a TLR-4 and ICAM-1 dependent fashion, and is potentiated by neutropenia. ICAM-1 and/or TLR-4 inhibition may be a unique strategy to prevent sepsis-associated VT.

Abstract 35: DVT Inflammation Assessed by 18F-FDG-PET/CT Predicts Subsequent Vein Wall Scarring

Objective: While venous thrombosis (VT)-induced inflammation facilitates thrombus resolution, inflammation causes vein wall scarring (VWS). Recently, statins have shown to improve VT resolution and reduce VT inflammatory components. In this study, we hypothesized that early VT inflammation detected by 18F-FDG positron emission tomography/computed tomography (PET/CT) could predict subsequent late stage VWS, and would be attenuated by statin therapy. Methods: Stasis VT was induced in 8-12 week old male C57BL/6 mice (n=31) in either the right jugular vein (n=13) or inferior vena cava (IVC,n=18). Animals in the IVC VT cohort were randomized to statin (n=8) or control (n=10) treatment. Statin, rosuvastatin (5mg/kg), was administered by oral gavage, daily starting 24 hours prior to VT induction; control mice received saline. All mice underwent survival FDG-PET/CT venography imaging on day 2. FDG inflammation signals (standard uptake value=SUV) were measured in the thrombosed vein and compared to the sham-operated venous segments or treatment control. On day 14, mice were sacrificed and VT tissue was resected. Picrosirius red staining allowed measurement of collagen and vein wall thickness in VT sections. Results: FDG-PET/CT at day 2 revealed increased inflammation signal activity in jugular VT (SUV 1.43 ± 0.3 VT vs. 0.81 ± 0.3 contralateral vein, p&lt;0.0001). Statin-treated mice showed a trend of decreased inflammation signal at day 2 in the IVC VT models (SUV 1.02 ± 0.1 statin VT vs. 1.42 ± 0.2 control VT, p=0.07). Day 14 histological analysis revealed significantly reduced vein wall injury in statin-treated animals (thickness, 32±9.4 μm statin; vs. 56.2±14.7 μm control, p=0.02). Day 2 FDG-PET inflammation in VT correlated positively with the magnitude of day 14 VWS (jugular VT, Spearman r=0.62, p=0.02; IVC VT r=0.74, p&lt;0.001, respectively). Conclusions: Quantitative FDG-PET/CT imaging demonstrates that early in vivo VT inflammation predicts subsequent VWS, a driver of post-thrombotic syndrome (PTS). The overall findings strengthen: (i) the link between inflammation and PTS; (ii) the translational potential of FDG-PET inflammation to predict VWS and PTS; and (iii) the concept that statins and other anti-inflammatory therapies could reduce VWS and PTS.

Evaluation of the Vascular Surgical Complications of Renal Transplantation

Renal transplantation is the treatment of choice of end-stage renal failure. However, vascular surgical complications can compromise the functional prognosis of the transplant or even be life threatening in the short term. Since few data are available in the literature, the objective of this study was to evaluate the vascular surgical complications of renal transplantation. In a retrospective and monocentric study, the records of all the patients receiving a kidney transplant between January 2008 and December 2014 were reviewed. The demographic data and the follow-up of the patients who presented a vascular surgical complication in relation to their transplant were collected. Minor, intermediate, or major vascular complications were defined according to the need for monitoring, reoperation, or the risk of transplant loss or a life-threatening situation. Predictive factors of vascular complications were also looked for. Mean age was 50.9±15.0years, and 312 kidney transplants were carried out (205 men). Fifty vascular surgical complications (16.0%) were found. Among them, 23 vascular complications (7.4%) were major, including 6 (1.9%) which required transplantectomy, after 4 arterial thromboses (1.3%), 1 early venous thrombosis (0.3%), and 1 injury of the inferior vena cava (0.3%). Twelve complications (3.8%) were minor. Surgical revision was necessary in 76% of the vascular complications (n=38). The average follow-up of the transplanted population was 37.4±24.0month, 268 kidney transplants (85.8%) were functional and 21 patients (6.7%) returned to dialysis. Surgical complications were more frequent when the recipient had hypertension (P=0.02, OR=2.5; 95% CI [1.1-6.1]), in case of right kidney transplant (P=0.0004, OR=3.1; 95% CI [1.6-5.8]) and when the kidney hilum consisted of at least arteries (P=0.02, OR=10.0; 95% CI [1.3-34]). Male gender (P=0.03, OR=0.5; 95% CI [0.3-0.9]) as well as the choice of the common iliac arterial (P=0.001, OR=0.4; 95% IC [0.2-0.7]) and venous (P=0.002, OR=0.3; 95% IC [0.2-0.8]) axes to carry out the vascular anastomoses appeared as protective factors. The vascular surgical complications of kidney transplantation, especially thromboses, can be serious and lead to transplant loss. The expertise of vascular surgeons finds its place here and makes it possible to maintain low rates of vascular complications and loss of transplants.

Noninvasive Imaging of Early Venous Thrombosis by 19F Magnetic Resonance Imaging With Targeted Perfluorocarbon Nanoemulsions.

Noninvasive detection of deep venous thrombi and subsequent pulmonary thromboembolism is a serious medical challenge, since both incidences are difficult to identify by conventional ultrasound techniques. Here, we report a novel technique for the sensitive and specific identification of developing thrombi using background-free 19F magnetic resonance imaging, together with α2-antiplasmin peptide (α2AP)-targeted perfluorocarbon nanoemulsions (PFCs) as contrast agent, which is cross-linked to fibrin by active factor XIII. Ligand functionality was ensured by mild coupling conditions using the sterol-based postinsertion technique. Developing thrombi with a diameter<0.8 mm could be visualized unequivocally in the murine inferior vena cava as hot spots in vivo by simultaneous acquisition of anatomic matching 1H and 19F magnetic resonance images at 9.4 T with both excellent signal-to-noise and contrast-to-noise ratios (71±22 and 17±5, respectively). Furthermore, α2AP-PFCs could be successfully applied for the diagnosis of experimentally induced pulmonary thromboembolism. In line with the reported half-life of factor XIIIa, application of α2AP-PFCs>60 minutes after thrombus induction no longer resulted in detectable 19F magnetic resonance imaging signals. Corresponding results were obtained in ex vivo generated human clots. Thus, α2AP-PFCs can visualize freshly developed thrombi that might still be susceptible to pharmacological intervention. Our results demonstrate that 1H/19F magnetic resonance imaging, together with α2AP-PFCs, is a sensitive, noninvasive technique for the diagnosis of acute deep venous thrombi and pulmonary thromboemboli. Furthermore, ligand coupling by the sterol-based postinsertion technique represents a unique platform for the specific targeting of PFCs for in vivo 19F magnetic resonance imaging.

The role of galectin-3 and galectin-3–binding protein in venous thrombosis

AbstractGalectin-3–binding protein (gal3bp) and its receptor/ligand, galectin-3 (gal3), are secreted proteins that initiate signaling cascades in several diseases, and recent human proteomic data suggest they may play a role in venous thrombosis (VT). We hypothesized that gal3bp and gal3 may promote VT. Using a mouse stasis model of VT, we found that gal3bp and gal3 were localized on vein wall, red blood cells, platelets, and microparticles, whereas leukocytes expressed gal3 only. Gal3 was dramatically increased during early VT and gal3bp:gal3 colocalized in the leukocyte/endothelial cell interface, where leukocytes were partially attached to the vein wall. Thrombus size correlated with elevated gal3 and interleukin-6 (IL-6) vein wall levels. Recombinant gal3 promoted VT and increased vein wall IL-6 mRNA. Although recombinant gal3 restored the VT size in gal3−/− mice, it had no effect on IL6−/− mice, suggesting that gal3:gal3bp promotes VT through IL-6. Moreover, significantly fewer activated neutrophils were present in the gal3−/− vein walls. In a group of human patients, elevated circulating gal3bp correlated with acute VT. In conclusion, gal3bp:gal3 play a critical role in VT, likely via IL-6 and PMN-mediated thrombotic mechanisms, and may be a potential biomarker in human VT.

Blood Accessibility to Fibrin in Venous Thrombosis is Thrombus Age-Dependent and Predicts Fibrinolytic Efficacy: An In Vivo Fibrin Molecular Imaging Study.

Fibrinolytic therapy of venous thromboembolism (VTE) is increasingly utilized, yet limited knowledge is available regarding in vivo mechanisms that govern fibrinolytic efficacy. In particular, it is unknown how age-dependent thrombus organization limits direct blood contact with fibrin, the target of blood-based fibrinolytic agents. Utilizing high-resolution in vivo optical molecular imaging with FTP11, a near-infrared fluorescence (NIRF) fibrin-specific reporter, here we investigated the in vivo interrelationships of blood accessibility to fibrin, thrombus age, thrombus neoendothelialization, and fibrinolysis in murine venous thrombosis (VT). In both stasis VT and non-stasis VT, NIRF microscopy showed that FTP11 fibrin binding was thrombus age-dependent. FTP11 localized to the luminal surface of early-stage VT, but only minimally to subacute VT (p<0.001). Transmission electron microscopy of early stage VT revealed direct blood cell contact with luminal fibrin-rich surfaces. In contrast, subacute VT exhibited an encasing CD31+ neoendothelial layer that limited blood cell contact with thrombus fibrin in both VT models. Next we developed a theranostic strategy to predict fibrinolytic efficacy based on the in vivo fibrin accessibility to blood NIRF signal. Mice with variably aged VT underwent FTP11 injection and intravital microscopy (IVM), followed by tissue plasminogen activator infusion to induce VT fibrinolysis. Fibrin molecular IVM revealed that early stage VT, but not subacute VT, bound FTP11 (p<0.05), and experienced higher rates of fibrinolysis and total fibrinolysis (p<0.05 vs. subacute VT). Before fibrinolysis, the baseline FTP11 NIRF signal predicted the net fibrinolysis at 60 minutes (p<0.001). Taken together, these data provide novel insights into the temporal evolution of VT and its susceptibility to therapeutic fibrinolysis. Fibrin molecular imaging may provide a theranostic strategy to identify venous thrombi amenable to fibrinolytic therapies.

Vascular complications of stereotactic radiosurgery for arteriovenous malformations

ObjectiveAlthough vasculopathy and de novo aneurysm formation are known complications of traditional radiation therapy, their occurrence following AVM SRS is rare and thus infrequently addressed in the literature. We sought to evaluate these phenomena through a review of our institutional experience. MethodsOur review afforded 32 patients treated with LINAC-based SRS over an eight year period. We noted obliteration rates, complication rates and long-term outcomes, with particular attention paid to follow-up angiographic studies. ResultsAfter a mean follow-up of 4.3 years, the overall obliteration rate was 50%, increasing to 87% for AVMs less than 3cm. Eight patients had nine hemorrhages following SRS (25%). One occurred in the context of a de novo arterial pseudoaneurysm and another in the context of a new venous varix. Two patients with post-SRS hemorrhage had intranidal aneurysms that were not as apparent on initial angiography. Two patients that did not suffer from latency period hemorrhage developed dysplastic changes of feeding arteries, and one patient suffered from early venous thrombosis with resultant permanent hemiparesis from infarction. After a mean follow-up of 4.3 years, 8 patients were clinically improved (25%), 19 were the same (59%), and 5 were worse (16%), including 2 that died as a result of latency period hemorrhage. ConclusionWhile radiosurgery of AVMs is safe and successful in the vast majority of cases, vasculopathic complications including de novo aneurysm and varix development, early venous occlusion and stenotic vasculopathy, while infrequent, can occur. Closer long-term angiographic surveillance of these patients may thus be warranted.

Protective effects of hypothermic ex vivo perfusion on ischemia/reperfusion injury and transplant outcomes

Hypothermic machine preservation (HMP) has been used in renal transplantation since the late 1960s with recent robust prospective, multicenter data showing lower rates of delayed graft function and improved graft survival. Although now clearly beneficial for renal transplantation, extrarenal machine perfusion has remained predominantly in preclinical investigations. Pancreatic HMP has drawn little clinical interest because HMP has been suggested to cause graft edema and congestion, which is associated with early venous thrombosis and graft failure. Early investigation showed no benefit of HMP in whole-organ pancreas transplant. One report did show that HMP increases islet cell yield after isolation. Preclinical work in liver HMP has been promising. Short- and long-term HMP has been shown to improve graft viability and reduce preservation injury, even in animal models of steatotic and donation after cardiac death. The first clinical study of liver HMP using a centrifugal dual perfusion technique showed excellent results with lower hepatocellular injury markers and no adverse perfusion-related outcomes. In addition, a dramatic attenuation of proinflammatory cytokine expression was observed. Further studies of liver HMP are planned with focus on developing a reproducible and standard protocol that will allow the widespread availability of this technology. Future research and clinical trials of novel organ preservation techniques, solutions, and interventions are likely to bring about developments that will allow further reduction of preservation-related ischemia/reperfusion injury and improved outcomes and allow safer utilization of the precious and limited resource of donor organs.

Early Draining Vein Occlusion After Gamma Knife Surgery for Arteriovenous Malformations

Increased signals on T2-weighted magnetic resonance imaging usually interpreted as radiation-induced changes or brain edema is a common short- to mid-term complication after Gamma Knife surgery (GKS) for intracranial arteriovenous malformations (AVMs), although its nature remains to be clarified. Early draining vein occlusion with resultant brain edema or hemorrhage, although well established in surgical series, was not described in radiosurgical literature until recently. To outline the incidence, clinical manifestations, and outcomes of this unusual complication in our series of 1256 AVM patients treated with GKS. From 1989 to 2008, 1400 patients underwent GKS for cerebral AVMs or dural arteriovenous fistulae at the University of Virginia. In 1256 patients, magnetic resonance imaging after GKS was available for analysis of radiation-induced changes and early draining vein occlusion. After GKS, 456 patients (36%) developed radiation-induced changes surrounding the treated nidi. Among these patients, 12 had early thrombosis of the draining vein accompanied by radiation-induced changes. Venous thrombosis occurred 6 to 25 months (median 11.6 months) after GKS. Three patients were asymptomatic on the image findings of venous occlusion and brain edema, 3 experienced headache, 1 had seizure and headache, and neurological deficits developed in 5. Patients with neurological deficits were treated with corticosteroids; 2 of the patients recovered completely, 1 still had slight hemiparesis, 1 had short-term memory deficits, and 1 died of massive intracerebral hemorrhage. Although venous structures are considered more radioresistant, endothelial damage accompanied by venous flow stasis might cause early venous thrombosis and premature venous occlusion after radiosurgery for AVMs. In our series, all patients had a favorable outcome except 1 with a fatal hemorrhage.