Increased venous versus arterial thrombosis in the Factor V Leiden mouse

BACKGROUND: Deep vein thrombosis (DVT) occurs with high prevalence in association with the Factor V Leiden (R506Q) mutation, whereas most evidence suggests no correlation with clinical arterial thrombosis. OBJECTIVE: This study compared arterial to venous thrombosis in the mutationally analogous Factor V Leiden mouse. METHODS: Three separate vascular thrombosis models were evaluated in Fv(+/+) (wild-type), Fv(Q/+) (heterozygous) and Fv(Q/Q) (homozygous) Factor V Leiden mice. RESULTS: In a FeCl(3)-induced arterial thrombosis model, no statistical differences among the three genotypes were found in the time to thrombotic occlusion. In contrast, Fv(Q/+) and Fv(Q/Q) mice demonstrated larger femoral vein thrombi at 30 and 60 min compared to wild-types, with Fv(Q/Q) mice having statistically larger thrombi than both wild-type and Fv(Q/+) mice at 10 and 60 min and 24 h (p<0.05). In a model of thrombotic occlusion following arterial and venous anastomotic repair, both Fv(Q/+) and Fv(Q/Q) mice had higher rates of venous thrombosis than wild-types, but only Fv(Q/Q) homozygotes showed a statistically greater arterial occlusion rate than wild-types. CONCLUSION: The Factor V Leiden mouse demonstrated a greater propensity for venous vs. arterial thrombosis, paralleling clinical epidemiologic findings and supporting its use for research on deep vein thrombosis.     

Individual propensity for thrombosis: comparison of venous and arterial circulations

Introduction

The pathogenesis of venous thrombosis has been attributed to complex interaction between environmental and inherited variables. A basal predisposition for venous thrombophilia independent of environmental variables has not been previously defined experimentally. Both to address the existence of an individual propensity to venous thrombosis and to establish an animal model in which variables governing this propensity could be tested, we provoked venous thrombi in a cohort of pigs of uniform size and age. We furthermore sought to determine whether the thrombotic propensity in the venous circulation is associated with similar propensity for arterial thrombosis.

Materials and methods

Bilateral iliac venous stents were deployed and 2 h later, thrombi were harvested and weighed. The thrombotic response was compared to carotid arterial thrombi generated by crush injury within the same pig. Venous and arterial thrombus platelet deposition were measured by scintillation detection of autologous ¹¹¹In-platelet content.

Results

In a cohort of 27 pigs, venous thrombus weights and platelet content varied over greater trrhan 10-fold range from least to greatest responders. There was strong intra-individual correlation of thrombus platelet deposition (r = 0.86; p = 0.008) and thrombus weights (r = 0.68; p = 0.015) between stented iliac vein pairs. Venous thrombosis correlated with whole blood platelet counts but not carotid platelet-rich thrombus formation.

Conclusions

The wide variation in venous thrombotic response to a standardized injury appears to represent an intrinsic propensity of the individual. The poor correlation with arterial thrombosis implies unique mechanisms responsible for this propensity in arteries and veins.     

Protein Z levels and anti-protein Z antibodies in patients with arterial and venous thrombosis

INTRODUCTION: The thrombotic risk associated with protein Z (PZ) deficiency is unclear. Anti-protein Z (anti-PZ) has been described as a risk factor in unexplained embryo demise. The aim of our study was to evaluate a possible PZ deficiency and presence of anti-PZ antibodies on thrombotic diseases. MATERIAL AND METHODS: We performed a case-control study on 114 patients with preexisting arterial or venous thrombosis (50 and 64, respectively). Thrombosis was studied based on etiology (creating factor risk subgroups) and on specific thrombotic disease. RESULTS: PZ levels of patients were significantly lower compared to controls (1709+-761.3 ng/mL vs. 2437+-964.7 ng/mL P=0.001). The high arterial risk factor subgroup showed the lowest PZ level (1267.5+-609 ng/mL) whereas the rest of arterial and venous etiological subgroups presented similar PZ levels. Patients with peripheral artery disease had the lowest PZ level (1022+-966 ng/mL). The rest of arterial and venous thrombotic diseases presented similar PZ levels. A significant increased risk for arterial and venous thrombosis for the lowest (<1685 ng/mL) quartile of PZ has been founded (OR:52, P=0.001 and OR:18, P=0.007, respectively). Anti-PZ antibodies were negative in the majority of patients, although mean anti-PZ IgG antibody levels in the arterial thrombosis group were significantly higher compared to venous thrombosis and control groups (P=0.05 and P=0.005, respectively). CONCLUSIONS: The results suggest that both arterial and venous thrombotic events are related to low PZ levels and that low PZ concentrations are associated with thrombosis in our study. In arterial thrombosis our findings strengthen previous studies that related low PZ levels to atherosclerotic disease. Anti-PZ antibodies do not seem to play a potent role in thrombosis.     

Antiphospholipid antibodies and thrombosis

Antiphospholipid syndrome is an autoimmune disease which combines vascular thrombosis and/or pregnancy complications with the presence of antiphospholipid antibodies. It could be a devastating and sometimes life-threatening condition. As vascular thrombosis presents as typical venous or arterial thromboembolism diagnosis is based on laboratory data. Therefore proper performance and interpretation of laboratory tests is crucial. Broader knowledge about clinical and laboratory aspects of the syndrome and their associations are essential for proper evaluation and management of the patients.     

脑静脉系统血栓形成诊断与治疗

正脑静脉系统血栓形成(CVT)最常发生于静脉窦,也可发生于皮质静脉和深静脉,发病率较低,静脉性卒中约占全部脑卒中的0.5%,成人和儿童发病率无明显差异[1],女性明显高于男性、男女比例约为1∶3,成年女性发病年龄明显低于成年男性(发病年龄分别为34和42岁)[2]。病因学研究显示,服用避孕药、妊娠期和产褥期(特别是妊娠期最后3个月和产后)、外伤、感染、肿瘤等均与脑静脉系统血栓形成密切相关[1,3-4]。分子水平研究显示,G20210A基     

Cerebral venous thrombosis mimicking acute unilateral vestibulopathy

We report a patient with cerebral venous thrombosis who presented with acute onset of severe prolonged vertigo, nausea, vomiting, unilateral decreased caloric response and occipital headache, simultaneously with acute venous cerebral infarcts on brain MRI. Although the patient had occipital headache, overall symptoms and signs closely mimicked those of acute unilateral vestibulopathy. Cerebral venous thrombosis should be considered in the differential diagnosis of acute unilateral vestibular syndrome.     

外伤性颅内静脉窦血栓诊治体会

目的 探讨外伤性颅内静脉窦血栓形成的诊断及治疗方法。 方法 回顾性分析经临床和影像学方法确诊的13例外伤性颅内静脉窦血栓形成患者资料,其中行血肿清除及去骨瓣手术3例,采取早期抗凝、静脉溶栓2例,静脉窦接触性溶栓介入治疗2例,病程较长、保守治疗效果不理想者行侧脑室—腹腔分流手术1例,余5例横窦栓塞患者没有症状或者症状轻微,行保守治疗。 结果 13例患者中10例治愈,2例存在局灶性症状,1例轻度智力障碍。术后3d～6个月8例复查DSA,3～6个月5例复查MRV,均通畅。结论外伤性颅内静脉窦血栓形成一旦确诊应尽早积极治疗,抗凝和溶栓治疗是目前主要治疗方法。     

Endovascular angioplasty and stent placement in venous hypertension related to dural arteriovenous fistulas and venous sinus thrombosis

Venous hypertension in lateral sinuses resulting from dural arteriovenous fistula (DAVF) and venous sinus thrombosis (VST) can manifest with severe neurological deficits, such as infarction or intracerebral hemorrhage. It has been proved that venous hypertension plays a significant role in the evolution and progression of DAVF and VST. The definite treatment in complicated conditions such as multiple DAVFs or multiple sinus occlusions is still unknown. Traditional transarterial embolization, transvenous embolization or radiosurgery alone has limited effects on these conditions. We reported one case with venous hypertension presenting with severe neurological symptoms. The case had quick clinical recovery after correction of venous hypertension by endovascular angioplasty and stent placement in occluded lateral sinuses. Accordingly, we propose this method can be an ideal treatment option either in single or staged therapy of venous hypertension related to DAVFs and VST.     

颅内静脉窦血栓形成13例

目的探讨颅内静脉窦血栓形成(CVST)的临床特点与治疗方法。方法分析13例CVST患者的临床、影像学特征及治疗方法。结果 13例多为中青年患者,临床表现头痛12例(92.3%),癫痫发作8例(61.5%)。11例腰穿显示脑脊液压力增高。头颅CT显示脑静脉窦异常5/13例(38.5%);MRI显示脑静脉窦异常7/13例(53.8%);MRV显示脑静脉窦异常7/12例(58.3%);DSA显示脑静脉窦异常6/6例(100%)。患者均应用脱水和抗凝治疗,部分予溶栓治疗,13例中5例基本痊愈,6例明显好转,2例遗留有不同程度的偏瘫、癫痫等症状。结论 CVST的临床特点是中青年人发生率高,以头痛、呕吐等颅高压症状为主要表现;MRI+MRV及DSA确诊率高;一旦确诊应及时予抗凝治疗,重症患者可行溶栓治疗。     

Inhibition of arterial thrombosis and platelet function by nafazatrom

Nafazatrom (1-[2-(naphthyloxy) ethyl]3-methyl-2-pyrayolin-5-one) has been shown to be a potent antithrombotic agent in experimental animals, but its mode of action is unknown. In this study, we examined its antithrombotic effect on arterial and venous thrombosis, vessel wall prostacyclin synthesis, and platelet aggregation in vivo and ex vivo in the rabbit. We found that arterial but not venous thrombus formation was significantly inhibited with low doses of nafazatrom. This antithrombotic effect was associated with a normalization of reduced platelet survival. Nafazatrom had no effect on basal or stimulated prostacyclin production but inhibited ADP- and collagen-induced platelet aggregation in vivo and ex vivo. This platelet effect was associated with a reduction in platelet thromboxane B₂ release and an inhibition of irreversible ADP-induced platelet aggregation.     

尿激酶联合替罗非斑在颅内静脉窦血栓形成介入性治疗中的应用

目的 探讨尿激酶联合替罗非斑血管内溶栓治疗颅内静脉窦血栓形成(CVST)的疗效和安全性. 方法 广州军区武汉总医院神经外科自2009年1月至2011年1月行尿激酶联合替罗非斑经微导管选择性静脉窦内溶栓、机械性碎栓治疗9例重症CVST患者,分析其临床资料和疗效. 结果 出院前8例患者脑脊液(CSF)压力正常,DSA检查显示7例患者静脉窦主干通畅,皮层静脉和深静脉恢复正常.1例部分再通,皮层静脉部分代偿.术中和术后未发生手术操作相关的并发症;出院时8例患者症状、体征得到改善,其中头痛消失7例,遗留轻度头痛1例.1例死亡. 结论 尿激酶联合替罗非斑经微导管选择性静脉窦内溶栓治疗是CVST安全、有效的治疗手段.     

Variations in platelet protein associated with arterial thrombosis

INTRODUCTION: Hyperactivity of platelets has been associated with thrombotic episodes by molecular mechanisms not yet elucidated. The present work aimed at identifying whether the platelet protein content from patients who had suffered an arterial thrombosis episode differed from that of platelets obtained from normal healthy donors. METHODS: Differential platelet protein profiles were determined by 2-dimensional (2-D) gel electrophoresis and Western blot analysis of total platelet lysates. Identification of differentially expressed proteins was carried out by mass spectrometry (MALDI-TOF). RESULTS: We found a decreased platelet content of three protein spots in patients of arterial thrombosis: integrin linked kinase (ILK), fructose bisphosphate aldolase (aldolase) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) whereas the content of four other protein spots was increased: actin binding protein, coronine like (p57), non-muscle myosin heavy chain (NMMHC-A), pyruvate kinase M2 isoenzyme (PK) and phosphoglycerate kinase (PGK). The variations in ILK, GAPDH and PK were validated by Western blot analysis. The proteins showing a decreased platelet content in arterial thrombosis patients are associated with the cytoskeletal insoluble fraction and the detected increase in some proteins seems to be due to the generation of peptides caused by a limited proteolysis. Differences in the protein profiles of circulating platelets from arterial thrombosis were maintained months after the acute thrombotic event and disappear in the long term. CONCLUSIONS: The observed variations in some platelet proteins suggest the existence of a perturbation in the cytoskeletal organization and increased proteolysis, both indicative of a platelet pro-active state, persistent after the thrombotic event.     

Validity of standard gamble estimated quality of life in acute venous thrombosis

Introduction

The standard gamble is considered the ‘gold standard’ technique for measuring quality of life. We recently used the standard gamble to estimate quality of life in acute venous thrombosis, and found unexpected variability in the responses. The current study aimed to explore the reasons for variability by comparing the standard gamble technique in patients with acute venous thrombosis to other quality of life measurement tools.

Materials and Methods

Thrombosis clinic patients treated for venous thrombosis were eligible to participate. Patients evaluated their current health state by performing a standard gamble interview, reporting on a visual analogue scale, completing the SF-36 and disease specific questionnaires (PEmb-Qol and VEINES-QOL/Sym). Validity was assessed by correlating the standard gamble utilities with the other methods. Test-retest reliability, responsiveness and acceptability were also assessed.

Results

Forty-four patients were interviewed, with 16 attending for a repeat interview. The median standard gamble utility was 0.97 (0.84-1.0), SF-6D 0.64 (0.59 - 0.80) and visual analogue score 70 (60 - 80). Participants with pulmonary embolism had lower standard gamble estimates than those with deep vein thrombosis. There was good discriminant validity in that the standard gamble estimates were not associated with risk taking behavior, negative outlook, sex or education. Test-retest reliability with the standard gamble was moderate and there was evidence of a ceiling effect.

Conclusions

Standard gamble utilities are higher than other methods of measuring quality of life in venous thrombosis. The choice of utility values adopted in studies will impact on future economic studies.     

A new in vivo model of arterial thrombosis: The effect of administration of ticlopidine and verapamil in dogs

An in vivo model of arterial thrombosis was developed in which either polytetrafluoroethylene (PTFE [Gore-Tex]) or autologous vein grafts were used to replace a segment of the femoral arteries of dogs. In one series of studies, 5 cm of PTFE and 5 cm of autologous femoral vein were used in each animal and blood flow was resumed for 1 hour. ¹¹¹In-labeled autologous platelets accumulated in greater amounts on the PTFE grafts (93.6 × 10⁶ platelets/cm) than on the vein grafts (2.6 × 10⁶ platelets/cm) (P<0.001). Orally administered ticlopidine (30 mg/kg/day for 2 days), an established inhibitor of platelets, reduced platelet deposition on the PTFE grafts to 10.5 × 10⁶ platelets/cm (P<0.01). In a second series of studies, PTFE grafts were interposed on both sides in each animal, and blood flow was resumed for 3 hours. With intravenously administered verapamil, a calcium antagonist, given perioperatively at 7.5 ug/kg/min, 12 of 16 grafts in eight dogs were patent compared with only 2 of 16 grafts in eight control dogs ($\text{P}$<0.001). Furthermore, platelet deposition on the grafts was reduced from 1,090 × 10⁶ platelets/cm to 303 × 10⁶ platelets/cm ($\text{P}$<0.001). Thus, both ticlopidine and verapamil are effective antithrombotic agents as a result of their inhibition of platelet activity in this model, and these results provide further evidence of a central role for calcium in platelet activation.     

脑静脉窦血栓形成伴颅内出血的治疗分析

目的 对比单纯抗凝和机械取栓联合局部溶栓治疗颅内静脉窦血栓形成(CVST)伴颅内出血患者的效果。方法 回顾性分析2014年6月-2018年6月武汉大学中南医院神经内科收治的28例CVST伴颅内出血患者的病例资料,根据其治疗方式分为单纯抗凝组(12例)和机械取栓组(机械取栓+局部溶栓+抗凝组16例),比较2组患者临床疗效、再通情况及预后。结果 机械取栓组的临床疗效、血管再通情况及预后均优于单纯抗凝组(P均<0.05),单纯抗凝组治疗后均未发现新发出血灶,机械取栓组仅有1例术后出现阴道出血。结论 对于合并有颅内出血的CVST患者,机械取栓联合局部溶栓治疗能有效促进静脉血流的恢复,缓解临床症状和改善预后。     

Evaluation of two experimental venous thrombosis models in the rat

An evaluation of the experimental model of venous thrombosis is an essential part of determination of the antithrombotic efficacy of novel antithrombotics. One of the most important parts of model evaluation is determination of thrombogenic stimuli. In this study, the construction of dose–response curves as an approach toward determination of appropriate thrombogenic stimuli in two experimental venous thrombosis models in the rat is described. By utilizing this approach, thrombogenic stimuli were successfully determined in a complete stasis combined with hypercoagulability induced venous thrombosis model (model 1) and in a partial stasis combined with vessel injury induced venous thrombosis model (model 2) in the rat. Beside complete or partial stasis, 600 μg/kg of thromboplastin or 7 μl of 6% w/v solution of ferric chloride was chosen for triggering formation of thrombus in models 1 and 2, respectively. At this thrombogenic stimulus, model 1 appeared to be more sensitive for evaluation of the effect of novel antithrombotic agents than model 2. Furthermore, we provided the evidence that the time of performance of the experiment in model 2 did not have a statistically significant impact on thrombus weight. Therefore, a randomized study design could be employed for the evaluation of the antithrombotic efficacy of novel antithrombotics. Moreover, quantification of thrombus weight was inspected, and thrombus wet weight proved to be the most convenient way of evaluation of thrombotic response.     

颅内静脉窦血栓形成的临床及影像学诊断25例报道

目的 研究颅内静脉窦血栓形成的病因、临床特点、特别是影像学的表现。方法 回顾性分析25例已确诊的静脉窦血栓形成患者（男2例,女23例）的临床资料及影像学特点,包括发病原因、临床表现、实验室检查及影像学头部CT、磁共振成像（MRI）和磁共振血管成像（MRA）的异常表现。结果 25例本病患者除2例男性外,余23例均有明确病因,如妊娠期、产褥期、口服避孕药等,临床表现以亚急性颅压高症状为主;部分头部CT可见条索征及空三征,MRI特征性表现为T1、T2加权像窦内异常高信号,MRA示栓塞的静脉窦未显影。结论 颅内静脉窦血栓形成患者多可找到明确病因,临床表现多样,无特异性,MRI/MRA可帮助确诊。     

Impact of anticoagulation status on recanalization and outcome of cerebral venous thrombosis

Effective anticoagulation status may determine the recanalization and outcome of cerebral venous thrombosis (CVT). We report impact of anticoagulation status on recanalization and outcome of CVT. This is a retrospective study on 126 patients with CVT diagnosed on magnetic resonance venography (MRV). Their clinical features and risk factors were noted. The data were retrieved from a prospectively maintained registry, and international normalized ratio (INR) was noted after discharge till 3 months. All the patients were on acenocoumarol. Based on INR value, patients were categorized as Group A (effective anticoagulation INR within the therapeutic range or above) and Group B (ineffective anticoagulation INR > 50% below the therapeutic range). A repeat MRV at 3 months was done for recanalization. Outcome at 3 months was evaluated using modified Rankin Scale (mRS), and categorized as good (mRS ≤ 2) and poor (mRS 2 or more) 101(80.2%) patients were in group A and 25(19.8%) in group B. Their demographic, risk factors, magnetic resonance imaging (MRI) and MRV findings were comparable. On repeat MRV, recanalization occurred in 22/24(91.7%); 15(88%) in group A and 7(100%) in group B. Recanalization was independent of coagulation status. Seven (5.6%) patients died and 107(84.9%) had good outcome; 85(84.2%) in group A and 22(88%) in group B. Kaplan Meier analysis also did not reveal survival or good outcome benefits between the groups. In CVT, outcome and recanalization at 3 months are not dependent on coagulation status. Further prospective studies are needed regarding duration of anticoagulant and its impact on recanalization and outcome.     

The impact of venous thrombosis on quality of life

Quality of life (QOL) is increasingly seen as an important outcome in clinical care. Etiology, diagnosis, and management of venous thrombosis have been studied extensively, but only few studies have examined the impact of venous thrombosis on quality of life. The purpose of this study was to examine the impact of venous thrombosis on quality of life in a well-defined population of patients with venous thrombosis, by using both a generic and a disease-specific quality of life measure. A total of 45 patients from the thrombosis clinic of the University of Vermont in Burlington, VT, returned a mailed questionnaire including the Short-Form 36 (SF-36) and a disease-specific venous thrombosis-quality of life (VT-QOL) questionnaire about the problems faced by patients with venous thrombosis. The sample consisted of 13 men (28.9%) and 32 women (71.1%). The mean age was 44.1 years, with a range from 21 to 80 years. Compared with population norms of a general U.S. population that were adjusted for age and sex (N= 2463), venous thrombosis patients scored significantly lower (p < 0.05) on all subscales of the SF-36. Patients with the postthrombotic syndrome (PTS) appeared to have more impairment in their quality of life as measured by both the SF-36 and the disease-specific questionnaire. All correlations between the SF-36 subscales and the subscales of the VT-QOL were significant, most of them on a p < 0.01 level. Given the impact of venous thrombosis and the postthrombotic syndrome on quality of life, assessment of QOL should be included in future studies on the outcome of venous thrombosis.