Differences in fibrin fiber diameters in healthy individuals and thromboembolic ischemic stroke patients

Cerebrovascular disease is one of the leading causes of death and the cause of long-term adult disability. An important characteristic of thromboembolic ischemic stroke is a prothrombotic or hypercoagulable state and altered fibrin clot structure, whereas a resistance to fibrinolysis is also present. An expansive fibrin network is created when adding thrombin, and in stroke, the network appears thickened, netted and matted, compared with that of healthy individuals. Although this is clearly visible in micrographs of patients, there is a need to quantify the changes. The current study, therefore, investigates fibrin fiber diameters in stroke patients and compares it to healthy individuals. The fiber diameters were measured in nanometres, with University of Texas Health Science Center at San Antonio (UTHSCSA) Image Tool. A total of 100 measurements were done for each of the 12 patients in the healthy control group, and the same number of measurements was done for 12 stroke patients. These measurements were statistically analysed with NCSS 2007, using a significance level of 0.05. Normality was assessed with the Shapiro-Wilk W test and the thickest and thinnest fiber of each individual in the two groups was quantified and differences between groups were assessed with the Student's t-test. Results showed that there is a statistical difference in fibrin fiber thickness during thromboembolic ischemic stroke. We conclude that the changed coagulation and hemostasis, typically associated with stroke, causes a statistically relevant change in fibrin thickness, and that this netted and matted network is more resistant to lyses.     

The changed ultrastructure of fibrin networks during use of oral contraception and hormone replacement

Contraceptives and hormone replacement have been extensively used since the late 1950s. However, adverse effects are common and include an increased risk of cardiovascular diseases, including thrombo-embolic diseases. Previous research has shown that ultrastructure of fibrin networks may provide great insight regarding the thrombotic potential of patients. The current study investigates the scanning electron microscopy (SEM) ultrastructure of fibrin networks of individuals using oral contraceptive therapy as well as individuals using hormone replacement. We compare micrographs of these two groups with micrographs of young, healthy individuals not using oral contraception. Platelet rich plasma and thrombin was used to prepare the fibrin clots. Here we show that during contraceptive and hormone replacement use, a netted fibrin layer forms. We suggest that oestradiol use causes fibrin network changes and these changes can be seen using SEM technology. These changes may provide further evidence regarding the increased occurrence of thrombotic events during contraceptive and hormone replacement therapy.     

Studies on the ultrastructure of fibrin lacking fibrinopeptide B (beta- fibrin)

Release of fibrinopeptide B from fibrinogen by copperhead venom procoagulant enzyme results in a form of fibrin (beta-fibrin) with weaker self-aggregation characteristics than the normal product (alpha beta-fibrin) produced by release of fibrinopeptides A (FPA) and B (FPB) by thrombin. We investigated the ultrastructure of these two types of fibrin as well as that of beta-fibrin prepared from fibrinogen Metz (A alpha 16 Arg----Cys), a homozygous dysfibrinogenemic mutant that does not release FPA. At 14 degrees C and physiologic solvent conditions (0.15 mol/L of NaCl, 0.015 mol/L of Tris buffer pH 7.4), the turbidity (350 nm) of rapidly polymerizing alpha beta-fibrin (thrombin 1 to 2 U/mL) plateaued in less than 6 min and formed a "coarse" matrix consisting of anastomosing fiber bundles (mean diameter 92 nm). More slowly polymerizing alpha beta-fibrin (thrombin 0.01 and 0.001 U/mL) surpassed this turbidity after greater than or equal to 60 minutes and concomitantly developed a network of thicker fiber bundles (mean diameters 118 and 186 nm, respectively). Such matrices also contained networks of highly branched, twisting, "fine" fibrils (fiber diameters 7 to 30 nm) that are usually characteristic of matrices formed at high ionic strength and pH. Slowly polymerizing beta-fibrin, like slowly polymerizing alpha beta-fibrin, displayed considerable quantities of fine matrix in addition to an underlying thick cable network (mean fiber diameter 135 nm), whereas rapidly polymerizing beta-fibrin monomer was comprised almost exclusively of wide, poorly anastomosed, striated cables (mean diameter 212 nm). Metz beta-fibrin clots were more fragile than those of normal beta-fibrin and were comprised almost entirely of a fine network. Metz fibrin could be induced, however, to form thick fiber bundles (mean diameter 76 nm) in the presence of albumin at a concentration (500 mumol/L) in the physiologic range and resembled a Metz plasma fibrin clot in that regard. The diminished capacity of Metz beta-fibrin to form thick fiber bundles may be due to impaired use or occupancy of a polymerization site exposed by FPB release. Our results indicate that twisting fibrils are an inherent structural feature of all forms of assembling fibrin, and suggest that mature beta-fibrin or alpha beta-fibrin clots develop from networks of thin fibrils that have the ability to coalesce to form thicker fiber bundles.     

Cancer‐associated ischemic stroke is associated with elevated d‐dimer and fibrin degradation product levels in acute ischemic stroke with advanced cancer

Aim: Although several studies have reported various causes of ischemic stroke in patients with cancer, only a few have evaluated the clinical relevance of ischemic stroke pathogenesis to cancer. The aim of the present study was to elucidate the clinical characteristics of cancer‐associated ischemic stroke. Methods: We evaluated 154 ischemic stroke patients without cancer and 57 ischemic stroke patients with cancer who had either received continuous treatment for cancer within 5 years before to the onset of ischemic stroke, or who had been diagnosed with cancer within 1 year after the onset of ischemic stroke. Cancer patients were grouped into “cancer‐associated ischemic stroke,” the “conventional ischemic stroke,” or “other.” Results: A total of 15 patients (26%) were classified into the cancer‐associated ischemic stroke in cancer patients. In univariate analysis of the cancer‐associated ischemic stroke and the others, there were significant differences in the prevalence of hypertension, hyperlipidemia and advanced cancer (clinical stage IV), and the levels of d ‐dimer, fibrin degradation product and hemoglobin. With multivariate regression analysis of those factors, the prevalence of hypertension, hyperlipidemia and advanced cancer (clinical stage IV), and the levels of d ‐dimer and fibrin degradation product remained as statistically independent factors, which were associated with cancer‐associated ischemic stroke (n = 111, χ² = 67.21, P < 0.0001). Conclusion: In acute ischemic stroke, the cancer‐associated ischemic stroke is associated with elevated d ‐dimer and fibrin degradation products, even after controlling hypertension, hyperlipidemia and advanced cancer (clinical stage IV). Geriatr Gerontol Int 2012; 12: 468–474.     

应重视急性缺血性卒中动静脉联合溶栓治疗的研究

目前，发病后3h行的静脉内溶栓治疗疗效仍然是明显的，并获准应用于临床急性缺血性卒中的标准溶栓治疗方法。然而，静脉内溶栓治疗对颈内动脉、大脑中动脉M1段等大血管闭塞的再通率很低，疗效欠佳；而动脉内溶栓治疗较静脉内溶栓虽有较高的再通率，但其优点却被时间耽误所抵消。动、静脉联合溶栓治疗兼有静脉内溶栓治疗的快速和动脉内溶栓治疗的高再通率，似乎是解决血管闭塞问题的一种好方法。     

脂蛋白相关磷脂酶A2与缺血性卒中

人血浆脂蛋白相关磷脂酶A2(lipoprotein-associated phospholipese A2,LP-PLA2)由成熟的巨噬细胞和淋巴细胞分泌,主要与低密度脂蛋白结合.近年来的研究表明,Lp-PLA2在动脉粥样硬化形成过程中起着重要作用,其基因多态性与缺血性卒中发生相关,其特异性抑制剂具有抗动脉粥样硬化作用.Lp-PLA2可能是缺血性卒中的新型独立危险因素和治疗靶标.     

Incorporation of fibrin molecules containing fibrinopeptide A alters clot ultrastructure and decreases permeability

Previous studies have shown that a heterozygous mutation in the fibrinogen Aalpha chain gene, which results in an Aalpha R16C substitution, causes fibrinolytic resistance in the fibrin clot. This mutation prevents thrombin cleavage of fibrinopeptide A from mutant Aalpha R16C chains, but not from wild-type Aalpha chains. However, the mechanism underlying the fibrinolytic resistance is unclear. Therefore, this study investigated the biophysical properties of the mutant fibrin that contribute to fibrinolytic resistance. Fibrin clots made from the mutant fibrinogen incorporated molecules containing fibrinopeptide A into the polymerised clot, which resulted in a 'spiky' clot ultrastructure with barbed fibrin strands. The clots were less stiff than normal fibrin and were cross-linked slower by activated FXIII, but had an increased average fiber diameter, were more dense, had smaller pores and were less permeable. Protein sequencing showed that unclottable fibrinogen remaining in the supernatant consisted entirely of homodimeric Aalpha R16C fibrinogen, whereas both cleaved wild-type alpha chains and uncleaved Aalpha R16C chains were in the fibrin clot. Therefore, fibrinolytic resistance of the mutant clots is probably a result of altered clot ultrastructure caused by the incorporation of fibrin molecules containing fibrinopeptide A, resulting in larger diameter fibers and decreased permeability to fibrinolytic enzymes.     

Prevention of ischemic stroke

The primary risk factors for stroke are known, and attention to primary care of these disorders should reduce the incidence of stroke significantly. Control of hypertension, diabetes, and hyperlipidemia have all been shown to reduce the rate of stroke. Identification of potential cardioembolic sources of stroke, particularly atrial fibrillation, can prevent stroke with appropriate application of anticoagulation. Duplex Doppler B-mode sonography can establish the extent of carotid artery disease in patients with cervical bruit or risk factors for atherosclerosis, and indicate which conditions should be managed medically or surgically. Patients with a history suggestive of transient ischemic attacks can also be screened noninvasively with duplex sonography to determine if they have a critical carotid stenosis and require carotid endarterectomy. New advances in platelet antiaggregant therapy with ticlopidine, clopidegril, and the combination of aspirin with dipyridamole have also reduced the rate of stroke to a greater degree than standard treatment with aspirin. The incidence of this devastating illness could possibly be reduced by 50% with attentive primary care management. The cardiologist is often involved in the treatment of patients at risk for stroke, and is in an ideal position to provide this care.     

Prevention of ischemic stroke

Opinion statement The primary risk factors for stroke are known, and attention to primary care of these disorders should reduce the incidence of stroke significantly. Control of hypertension, diabetes, and hyperlipidemia have all been shown to reduce the rate of stroke. Identification of potential cardioembolic sources of stroke, particularly atrial fibrillation, can prevent stroke with appropriate application of anticoagulation. Duplex Doppler B-mode sonography can establish the extent of carotid artery disease in patients with cervical bruit or risk factors for atherosclerosis, and indicate which conditions should be managed medically or surgically. Patients with a history suggestive of transient ischemic attacks can also be screened noninvasively with duplex sonography to determine if they have a critical carotid stenosis and require carotid endarterectomy. New advances in platelet antiaggregant therapy with ticlopidine, clopidogrel, and the combination of aspirin with dipyridamole have also reduced the rate of stroke to a greater degree than standard treatment with aspirin. The incidence of this devastating illness could possibly be reduced by 50% with attentive primary care management. The cardiologist is often involved in the treatment of patients at risk for stroke, and is in an ideal position to provide this care.     

Rehabilitation after ischemic stroke in the elderly

The aim of the rehabilitation after stroke is the recovery of the best functioning, by stimulation of cerebral plasticity and functional compensation while preventing complications. The capacity of recovery in the ageing subject depends on previous physiological and psychological status, previous medical history, specially previous brain lesions, and stroke severity. Rehabilitation is best to be conducted in specialised Physical and Medicine Rehabilitation Units, in which the functional and vital prognosis is improved by specialised interdisciplinary teams. Its goal is to obtain the best autonomy possible in the usual environment. Age by itself should not be a criteria for admission in such units.     

Genetics of ischemic stroke

Genetic factors are important in the pathogenesis of cerebrovascular diseases. Stroke represents a multifactorial polygenic disorder where the role of environmental factors is quite well defined as opposed to the role of genetic factors which needs to be further elucidated. Several genes affecting hemostasis, renin-angiotensin system, nitric oxide production, homocysteine metabolism and lipid metabolism have been investigated in stroke even if with conflicting results. The genetic approach could permit, in the future, a better characterization of stroke patients and a more effective individual preventive and therapeutic approach.     

缺血性脑卒中的预防

过去的世纪,医学在为延长生命而拼搏。血栓病是人类的第一天敌,包括心肌梗死和脑梗死。过去的10年,心肌梗死病死率下降1/3;脑梗死病死率下降1/4。然而,我国在步入老龄化社会的同时,脑梗死的发病率呈上升趋势,发病年龄也趋于年轻化。2005年11月WHO统计公布全球脑卒中死亡人数为5     

缺血性卒中的神经保护

血管再通是缺血性卒中发病前几个小时的目标治疗，是神经保护(neuroprotection)的重要开端，使脑组织功能最大可能恢复的一系列治疗(medical management)，即神经保护的最终目标治疗还远远没有结束。几十年来，缺血性卒中的神经保护研究持续不断，虽然结果并不尽人意，甚至陷入种种困惑，但毕竟获得了阳性或阴性、肯定或否定、完全或不完全的实验证据，并一步步向最终目标靠近。     

儿童动脉性缺血性卒中

动脉性缺血性卒中(arterial ischemic stroke,AIS)是儿童获得性脑损伤的一个重要原因,具有较高的病死率和残疾率.儿童AIS在病因学和危险因素方面不同于成年人缺血性卒中,其识别具有挑战性,常发生明显的诊断延误.文章对儿童AIS的危险因素、诊断性评价和治疗进行了综述.     

缺血性卒中的抗氧化治疗

氧化应激是缺血性卒中神经元损害的重要病理学机制之一,抗氧化治疗已成为缺血性脑损伤治疗的重要措施之一.文章就缺血性卒中的抗氧化治疗进展进行了综述.     

儿童动脉性缺血性卒中

卒中是儿童残疾和死亡的一个重要原因,其危险因素与病理生理学过程与成年患者存在显著差异.儿童动脉性缺血性卒中(arterial ischemic stroke,AIS)的常见危险因素包括脑动脉病、心脏疾病、血液系统和代谢性疾病、感染以及遗传因素.AIS的临床表现因年龄、基础病因和卒中部位而异.在经过充分检查之后,90％以...     

非瓣膜病性心房颤动伴缺血性卒中的复发分析

目的探讨非瓣膜病性心房颤动（房颤）伴缺血性卒中患者的复发及其影响因素。方法回顾性分析1992—2002年住院非瓣膜病性房颤伴缺血性卒中患者386例,随访收集有关临床资料,进行复发分析并研究其复发的相关因素。结果非瓣膜病性房颤伴缺血性卒中患者的10年累计复发率为34％,Cox回归单因素分析发现,高血压、糖尿病、短暂性脑缺血发作（TIA）、高脂血症、附壁血栓是非瓣膜病性房颤伴缺血性卒中患者复发的危险因素,Cox回归多因素分析发现高血压病,TIA发作史与附壁血栓为非瓣膜病性房颤合并缺血性卒中复发的独立危险因素;而阿司匹林与华法林治疗对非瓣膜病性房颤合并缺血性卒中复发有保护作用。结论高血压病、TIA发作史与附壁血栓为非瓣膜病性房颤合并缺血性卒中复发的独立危险因素,阿司匹林与华法林治疗对非瓣膜病性房颤合并缺血性卒中复发有保护作用。     

Antithrombotic drugs in the prevention of ischemic stroke

Stroke prevention cannot be dissociated from cardiovascular prevention in general. It is based on the correction of vascular risk factors, particularly hypertension and tobacco smoking, and on antithrombotic drugs which tackle the thrombo-embolic process which is the immediate cause of the ischemic event. Ischemic strokes exhibit considerable etiopathogenic diversity, the underlying cause modifying thrombus composition. In atherothrombotic brain infarction, platelets play a major role and antiplatelet drugs have a benefit/risk ratio better than that of oral anticoagulants, with a 25% reduction in the combined risk of ischemic stroke, myocardial infarction and vascular death. Antiplatelet drugs are also used in small artery diseases of the brain although the role of thrombosis is unknown and no specific trial has been devoted to this variety of cerebrovascular disease. In emboligenic cardiac diseases, atrial fibrillation in particular, stasis of the dilated left atrium favors coagulation phenomena, hence the much better efficacy of oral anticoagulants (presently vitamin K antagonists) both in primary and secondary prevention with a 70% risk reduction in cerebral infarction, compared with only 20% for aspirin. The expected benefit of antithrombotic drugs must be weighed against their inherent hemorrhagic risk, which is greatest for oral anticoagulants, slightly less for association of antiplatelet drugs and even less for each antiplatelet drug given alone. The use of antithrombotic drugs allows a targeted prevention of cerebral infarction. It is based on a triple case by case evaluation: that of the cause and of the risk it carries, that of the benefit expected from antithrombotic drugs, and that of their inherent hemorrhagic risk.