fibrin and Ischemia

This study aims to determine, based on existing data, whether the mechanism resulting in liver dysfunction in HELLP syndrome resembles that in Sinusoidal Obstruction Syndrome (SOS).. HELLP syndrome is a serious pregnancy disorder with high maternal and perinatal morbidity and mortality rates. Because of poor insight in its pathophysiology, particularly that of the liver involvement, clinical management is limited to symptomatic treatment, often followed by termination of pregnancy. SOS is a rare, potentially life-threatening complication of radio and/ or chemotherapy in the preparation of hematopoietic cell transplantation. The etiology of liver dysfunction in SOS is - unlike that in HELLP syndrome - better-understood and seems to be initiated by direct toxic damage and demise of endothelial cells, causing hepatic sinusoidal obstruction and ischemia.. We searched Pubmed, Embase and Cochrane for reports on the etiology of HELLP and SOS. This yielded 73 articles, with 14 additional reports from the references listed in these articles.. The dysfunctional placenta in women developing HELLP initiates a cascade of events that eventually results in liver dysfunction. The placenta releases, besides anti-angiogenetic factors, also necrotic debris and cell-free DNA, a mixture that not only induces systemic endothelial dysfunction as in preeclampsia, but also a systemic inflammatory response. The latter aggravates the endothelio-toxic effects in the systemic cardiovascular bed, amplifying the already increased pro-thrombotic conditions. Particularly in microcirculations with extremely low shear forces, such as in the hepatic sinusoids, this will facilitate microthrombi formation and fibrin deposition eventually resulting in obstruction of the sinusoids similar as in SOS. The latter causes ischemic damage and progressive demise of hepatocytes.. The available information supports the concept that the liver damage in HELLP and SOS results from sinusoidal ischemia, presumably resulting from partially overlapping pathophysiological mechanisms.

Topics: Complement System Proteins; Endothelium, Vascular; Female; Fibrin; HELLP Syndrome; Hepatic Veno-Occlusive Disease; Humans; Ischemia; Liver; Placenta; Pregnancy; Regional Blood Flow; Thrombotic Microangiopathies

The peritoneum is a serous membrane, which has a protective function for the contents of the abdominal cavity. It maintains homeostasis by allowing exchange of molecules and production of peritoneal fluid, thus providing an environment in which intra-abdominal organs can function properly. When traumatized, whether by surgery or due to inflammatory processes, a series of responses come into action to regenerate the injured part of the peritoneum. The inflammatory reaction causes influx of inflammatory cells but also activates resident mesothelial cells, ultimately leading to a fibrinous exudate. Depending on the severity of the trauma this exudate is transient due to fibrinolysis, or becomes more dense as a result of fibroblasts persisting, leading to fibrinous adhesions. A pivotal role is taken by the enzyme plasmin and its promotors and inhibitors; it is mainly the tissue-type plasminogen activator/plasminogen activator inhibitor ratio which determines the rate of fibrinolysis and therefore the rate of adhesion formation. The rate of injury determines the rate and extent of the inflammatory response to that injury; in its turn the inflammatory reaction determines the extent of adhesion formation. One should realize this when performing intra-abdominal surgery, which is in fact operating inside the peritoneal organ.

Topics: Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Homeostasis; Humans; Inflammation; Ischemia; Peritoneum; Postoperative Complications; Tissue Adhesions; Tissue Plasminogen Activator

We reviewed the histopathologic characteristics of DIC in autopsy cases. Typical hyaline microthrombi preferentially occurred in renal glomeruli, pulmonary microvasculature, splenic sinuses, adrenocortical capillaries and others, occasionally associated with degenerative or necrotic changes of parenchymal cells of respective organs partly due to ischemic effects of microthrombi and thromboemboli. Investigating the pathogenesis of microthrombi in hepatic sinusoids of rats intravenously injected with LPS (5 mg/kg B.W.) using double immunohistochemical reactions for LPS and fibrinogen, and electron microscopic observations, fibrin thrombi were largely formed around small necrotic foci of hepatocytes 1 hr after injection, which occurred in the very close vicinity to Kupffer cells phagocytizing LPS, and on the cytoplasmic surface of swollen Kupffer cells lading LPS 3 hr after injection. Neutrophils always aggregated in the necrotic foci. Thus, activated Kupffer cells by LPS seemed to play a central role in the development of fibrin thrombi in hepatic sinusoids of endotoxemic rats, through the activation of coagulation system probably via the expression of tissue factor by activated Kupffer cells.

Topics: Animals; Disseminated Intravascular Coagulation; Fibrin; Hemorrhage; Humans; Ischemia; Kidney Glomerulus; Lipopolysaccharides; Macrophages; Microcirculation; Thrombosis

During the last 25 years, cutaneous biologists have been particularly interested in abnormal cutaneous vascular patterns, the profusion of capillary anastomoses, the leakiness of venules, clotting, fibrinolysis, and blood viscosity. As a result, the effects of hypoxia and the factors that encourage new vessel proliferation are better understood than before. Only when the biologic behavior of the two extremes of growth from hypoplasia to hyperplasia is studied and compared can the blood supply of a tissue be understood. Hyperplastic tissues are seen in wounds, psoriasis, cancer, and in selected sites of chronic stasis and hypoxia where the vessels are extremely permeable, where blood cells easily escape, and where lymphatics dilate and proliferate. The proliferation of other tissues, such as endothelium, epithelium, mast cells, and probably of locally infective organisms, is also encouraged in hyperplasia. Moreover, fibrinolysis does not occur and fibrin is deposited, the electrostatic charge on the internal vascular surface becomes more positive, and the organ is more vulnerable to subsequent injury. Atrophic or hypoplastic tissues have a reduced cellular turnover and are less hypoxic. The vessels are less permeable, blood cells do not escape, there is only a slight tendency to clot, and fibrinolysis is often increased. Lymphatics are sparse and infection is not a feature. The electrostatic charge on the internal surface of the vessel is negative.

Topics: Animals; Blood Viscosity; Capillaries; Cell Membrane; Disseminated Intravascular Coagulation; Fibrin; Fibrinolysis; Humans; Hypoxia; Ischemia; Skin; Skin Neoplasms; Telangiectasis

Topics: Adenosine Diphosphate; Animals; Anti-Inflammatory Agents; Arteriosclerosis; Blood Coagulation; Blood Platelets; Blood Proteins; Blood Vessels; Collagen; Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Glass; Graft Rejection; Hemostasis; Humans; Ischemia; Kidney Transplantation; Platelet Adhesiveness; Platelet Aggregation; Thrombosis; Transplantation, Homologous

This literature review attempts to enumerate possible etiologies of postoperative peritoneal adhesions as well as to suggest preventitive measures. The theory that the cause of adhesions was development of fibrous tissue resulting from the destruction of serosa at surgery is discussed, but the author points out that numerous experimental and clinical experiences point to a more complicated etiology. Serosal defects do heal, and not necessarily through adhesion formation, as shown in experimental animals; therefore a new notion of the process of peritoneal repair was advanced which, simply stated, sees free-floating macrophages as the principal source of new serosa. So other areas and tissue types are probably the source of adhesions. The discussion of these other etiological factors include ischemic tissue as a source of adhesions and foreign body causes of granuloma and adhesions (primarily surgical glove powder). In terms of adhesion prevention, many approaches have been tried from using prophylactic agents to inhibit the formation of fibrin in peritoneal exudate (agents such as sodium citrate, heparin, and anticoagulants), use of enzymes and fibrinolytic agents, such as streptokinase and hyaluronidase, to introduction of inert polysiloxanes for prevention at the time of surgery. The use of cortisone, which has been reported to have good results, is also discussed. Finally, the control of distribution of adhesions by plicative techniques is enumerated. With the up-to-date knowledge that adhesions which develop after abdominal operations represent a vascular response by surrounding structures to the stimulus of ischemic tissue or foreign material within the peritoneal cavity, rather than a healing mechanism for serosal defects, a rational approach toward operating on adhesions is presented; this technique requires scrupulous surgical procedure, freedom from foreign body intrusion, the leaving open of serosal defects (rather than pulling together under tension), and, frequently, attempts to surgically ensure that the inevitable adhesion formation occurs in areas which are innocuous to adjacent structures.

Topics: Abdomen; Enzyme Therapy; Exudates and Transudates; Fibrin; Fibrinolytic Agents; Histamine H1 Antagonists; Humans; Hyaluronoglucosaminidase; Intestinal Obstruction; Ischemia; Peritoneal Diseases; Peritoneum; Postoperative Complications; Tissue Adhesions; Wound Healing

To report the intra-and postoperative complications and visual acuity outcomes in pars plana vitrectomy (PPV), phacoemulsification and intraocular lens (IOL) implantation in patients with cataract and proliferative diabetic retinopathy (PDR). A comparison of the combined versus two-step surgical approach is given.. Retrospective uncontrolled interventional clinical trial. Forty-eight eyes of 48 consecutive patients with PDR were included. Twenty-eight (58.3%) eyes with combined surgery and 20 (41.7%) eyes with sequential surgery were analyzed.. Postoperative follow-up time was between 6 and 63 months (mean: 18 months). 1) Combined surgery: Preoperative best-corrected visual acuity (BCVA) ranged from 20/200 to hand motions, and postoperative BCVA ranged from 20/30 to hand motions. BCVA improved in 17 eyes (60.7%), while in 7 (25%) eyes there was no change (> or =2 ETDRS lines) in VA, and in 4 (14.3%) eyes BCVA decreased. Postoperative complications included vitreous hemorrhage (VH) in 10 (35.7%) eyes, and fibrinous exudation in 9 (32.1%) eyes. 2) Two-step surgery: Preoperative BCVA ranged from 10/200 to light perception, and from 20/40 to light perception in the postoperative period. Best-corrected visual acuity improved in 15 (75%) eyes, remained the same in 4 (20%) eyes, and decreased in 1 (5%) eye. Postoperative complications included fibrinous exudation in 6 (30%) eyes, and VH in 3 (15%) eyes.. Combined PPV, phacoemulsification and IOL implantation as well as the two-step procedure are safe and effective for the management of cataract in PDR. Sequential surgery could be advantageous to BCVA outcomes by minimizing postoperative VH, which is significantly more frequent after combined surgery.

Topics: Adult; Aged; Aged, 80 and over; Cataract; Diabetic Retinopathy; Exudates and Transudates; Female; Fibrin; Follow-Up Studies; Humans; Intraoperative Complications; Ischemia; Lens Implantation, Intraocular; Macula Lutea; Male; Middle Aged; Phacoemulsification; Postoperative Complications; Retinal Detachment; Retrospective Studies; Time Factors; Visual Acuity; Vitrectomy; Vitreoretinopathy, Proliferative; Vitreous Hemorrhage

Treatment doses of heparins are not recommended for acute ischemic stroke. Despite this, their use in this setting is widespread. We investigated whether subgroups of patients with acute ischemic stroke and atrial fibrillation, identified by clinical, hemostatic (d-dimer, prothombin fragments(1+2) [F(1+2)], soluble fibrin monomer), or inflammatory (C-reactive protein [CRP]) variables might have a differential response to low molecular weight heparin (LMWH) over aspirin. In addition, we sought to identify factors associated with a poor clinical outcome at 3 months.. We conducted a post hoc subgroup analysis of a randomized, placebo-controlled, double-blind trial (Heparin in Acute Embolic Stroke Trial) designed to test the hypothesis that treatment doses of LMWH (dalteparin; 100 IU/kg BID) would be superior to aspirin (160 mg per day) in patients with acute ischemic stroke and atrial fibrillation. For the current analysis, 431 participants were included. The primary outcome measure was a poor outcome at 3 months, defined as death or dependency in activities of daily living. Using regression analysis, we determined whether any of the chosen variables were associated with a differential response to dalteparin (treatment interaction) or with poor outcome.. In the multivariable logistic regression model, none of the clinical, hemostatic, or inflammatory variables were associated with a significant treatment interaction. Stroke severity (odds ratio [OR], 1.09 [95% CI, 1.07 to 1.12]), increasing age (OR, 1.09 [CI, 1.05 to 1.14]), CRP level (OR, 1.32 [CI, 1.04 to 1.66]), and F(1+2) level (OR, 1.77 [CI, 1.07 to 2.91]) were independently associated with a poor outcome at 3 months.. Our study does not support the use of treatment doses of LMWH in any of the studied subgroups of patients with acute ischemic stroke and atrial fibrillation. Age, stroke severity, CRP, and F(1+2) were predictive of poor outcome at 3 months.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; C-Reactive Protein; Double-Blind Method; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Heparin, Low-Molecular-Weight; Humans; Ischemia; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Placebos; Prothrombin; Stroke; Time Factors; Treatment Outcome

The aim of this paper is to assess the feasibility and efficacy of fibrin in inducing neovascularization as an angiogenic substance and/or carrier for vascular endothelial growth factor (VEGF) in patients with limb ischemia.. Twenty-three patients with limb ischemia and referred for below the knee amputations were randomized for treatment: group 1, 7 patients received only a saline injection; group 2, 9 received intramuscular injection of fibrin and group 3, 7 received the fibrin composition with deferoxamine and added VEGF(165). The fibrin meshwork was introduced into the popliteal area of the diseased limbs using a dual syringe system (1 contained thrombin solution [1 mg, 5000 U] and 1 contained fibrinogen [1 mg, Baxter Hyland Immuno] solution). In group 3, Deferoxamine (100 microg) and 500 microg of VEGF(165) were added to the fibrinogen solution.. In the control group 5 patients had undergone below the knee amputation at the 3-6 month follow-up. Only 1 patient from Group 2 had below the knee amputation 5 months following Fibrin only administration. Clinical improvement was noted in all 8 patients following fibrin administration and in all 7 patients injected with the fibrin meshwork, deferoxamine and VEGF combination.. IM injection of fibrin is safe and appears to be an efficient method to treat limb ischemia. These findings indicate that use of fibrin may be a novel and simple method for inducing therapeutic angiogenesis.

Topics: Adult; Deferoxamine; Drug Therapy, Combination; Feasibility Studies; Fibrin; Fibrinogen; Humans; Injections, Intramuscular; Ischemia; Male; Middle Aged; Neovascularization, Physiologic; Pilot Projects; Vascular Endothelial Growth Factors

Stroke is one of the most prevalent diseases worldwide caused primarily by a thrombotic vascular occlusion that leads to cell death. To date, t-PA (

Topics: Extracellular Traps; Fibrin; Humans; Ischemia; Stroke; Thrombosis; Thrombotic Stroke

Ischemic acute kidney injury is common, deadly, and accelerates the progression of chronic kidney disease, yet has no specific therapy. After ischemia, reperfusion is patchy with early and persistent impairment in regional renal blood flow and cellular injury. We tested the hypothesis that intrarenal coagulation results in sustained renal ischemia following reperfusion, using a well-characterized model. Markedly decreased, but heterogeneous, microvascular plasma flow with microthrombi was found postischemia by intravital microscopy. Widespread tissue factor expression and fibrin deposition were also apparent. Clotting was accompanied by complement activation and inflammation. Treatment with exosomes derived from renal tubular cells or with the fibrinolytic urokinase, given 24 h postischemia when renal failure was established, significantly improved microvascular flow, coagulation, serum creatinine, and histological evidence of injury. These data support the hypothesis that intrarenal clotting occurs early and the resultant sustained ischemia is a critical determinant of renal failure following ischemia; they demonstrate that the coagulation abnormalities are amenable to therapy and that therapy results in improvement in both function and postischemic inflammation.

Topics: Acute Kidney Injury; Animals; Creatinine; Disease Models, Animal; Fibrin; Inflammation; Ischemia; Kidney; Reperfusion; Reperfusion Injury; Thromboplastin; Urokinase-Type Plasminogen Activator

Topics: Fibrin; Fibrin Clot Lysis Time; Humans; Ischemia; Thromboembolism; Thrombosis

Pro-angiogenic growth factors have been studied as potential therapeutics for cardiovascular diseases like critical limb ischemia (CLI). However, the translation of these factors has remained a challenge, in part, due to problems associated with safe and effective delivery. Here, we describe a hydrogel-based delivery system for growth factors where release is modulated by focused ultrasound (FUS), specifically a mechanism termed acoustic droplet vaporization. With these fibrin-based, acoustically-responsive scaffolds (ARSs), release of a growth factor is non-invasively and spatiotemporally-controlled in an on-demand manner using non-thermal FUS. In vitro studies demonstrated sustained release of basic fibroblast growth factor (bFGF) from the ARSs using repeated applications of FUS. In in vivo studies, ARSs containing bFGF were implanted in mice following induction of hind limb ischemia, a preclinical model of CLI. During the 4-week study, mice in the ARS + FUS group longitudinally exhibited significantly more perfusion and less visible necrosis compared to other experimental groups. Additionally, significantly greater angiogenesis and less fibrosis were observed for the ARS + FUS group. Overall, these results highlight a promising, FUS-based method of delivering a pro-angiogenic growth factor for stimulating angiogenesis and reperfusion in a cardiovascular disease model. More broadly, these results could be used to personalize the delivery of therapeutics in different regenerative applications by actively controlling the release of a growth factor.

Topics: Animals; Fibrin; Fibroblast Growth Factor 2; Hindlimb; Hydrogels; Ischemia; Mice; Neovascularization, Physiologic; Volatilization

To identify risk factors of disease severity and between mild and severe colon ischaemia (CI) patients and to improve clinical outcomes, this study aimed to explore a novel scoring model.. Retrospective analyses of hospital records between January 2009 and December 2019 were included. Clinical manifestations, mortality, Oakland score, laboratory tests, colonoscopy, and histopathology were collected. Risk factors of severe CI were determined by univariate and multivariate logistic regression and used for the predicting model.. A total of 203 patients with CI were included. Serum C-reactive protein (CRP) and albumin ratio (CAR) were much higher in the severe CI group compared with that of the mild CI group (3.33 ± 1.78 versus 0.68 ± 0.97,. The novel prognostic model was established to predict CI severity and clinical outcomes efficiently.Key messagesIn this article, we discuss the scoring model for clinical outcomes of colon ischaemia patients.In our study, the sensitivity and specificity of a novel scoring model are very high.Thus, laboratory tests (CRP albumin ratio), Oakland score, and histopathological findings (fibrin thrombi) can be assessed efficiently for colon ischaemia outcomes.

Topics: Albumins; C-Reactive Protein; Colon; Fibrin; Humans; Ischemia; Prognosis; Retrospective Studies; ROC Curve

Fibrin clot structure differs between healthy individuals and those following thromboembolic events. Dense and poorly lysable fibrin clots have also been reported in peripheral artery disease. We studied fibrin clot properties and its determinants in individuals with a history of acute lower limb ischemia (ALI) of unknown cause.. In this case-control study, we enrolled 43 patients who experienced ALI of unknown cause, and two age-and sex-matched reference groups: (1) patients with cryptogenic non-lacunar stroke (n = 43) and (2) individuals without any history of thromboembolism (n = 43, control group). Plasma fibrin clot properties, along with thrombin generation and fibrinolysis markers were assessed following ≥3 months of anticoagulation.. Compared with the control group, the ALI group exhibited more compact plasma fibrin clots (13.4% lower permeability [K. Patients who experienced ALI of unknown cause display a prothrombotic fibrin clot phenotype, including increased clot density and hypofibrinolysis associated with higher thrombin generation, which might suggest potential benefits from prolonged anticoagulation in this disease.

Topics: Case-Control Studies; Fibrin; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Ischemia

Hypolysible fibrin clots composed of tightly packed fibers characterize patients with peripheral artery disease (PAD) especially those with critical limb ischemia (CLI). Little is known about the impact of a prothrombotic clot phenotype on restenosis following endovascular revascularization in CLI. The goal of this study was to compare fibrin clot properties and their determinants in CLI patients with restenosis after endovascular treatment (ET) and those free of this complication.. 85 patients with CLI and restenosis within 1 year after ET on optimal pharmacotherapy and 47 PAD control patients without restenosis were included into the study. Plasma fibrin clot permeability (Ks, a measure of the average pore size in the fibrin network) and clot lysis time (CLT) with its potential determinants were determined. During follow-up, the composite endpoint including re-intervention, amputation and death was assessed.. Compared with the control group, patients with restenosis had reduced K. The increased thrombin formation and unfavorable fibrin clot properties occur in patients with CLI who experienced restenosis despite optimal endovascular and pharmacological therapy.

Topics: Aged; Aged, 80 and over; Extremities; Female; Fibrin; Fibrin Clot Lysis Time; Graft Occlusion, Vascular; Humans; Ischemia; Male; Mechanical Thrombolysis; Middle Aged; Peripheral Arterial Disease; Thrombin; Thrombosis

We evaluated the efficacy of sutureless laparoscopic partial nephrectomy (LPN), using a fibrin gel in order to minimize renal ischemia time and preserve kidney function.. Nineteen patients (mean age 58.3 ± 7.1) undergoing sutureless LPN using a fbrin gel were compared with a control group consisting of 21 patients (mean age 57.9 ± 7.5) subjected to LPN with standard suturing. Intraand post-operative data for the two groups were compared. The following parameters were recorded: patient demographics, Charlson Comorbidity Index, tumor characteristics according to the RENAL score, warm ischemia and operative times, estimated blood loss, mean hospital stay, post-operative complications referring to the Clavien-Dindo classification, renal function parameters pathologic and follow-up data. The main outcome measure was renal ischemia time and maintenance of kidney function.. Median warm ischemia time was 13 minutes (range 11-19) in the group treated with fibrin gel and 19 (range 17- 29) in the control group, with a statistically significant difference (p < 0.001). The two groups were homogeneous in terms of the Charlson Comorbidity Index (4.6 vs 4.8) and RENAL score (9.6 vs 9.4). Median operative time differed significantly in the two groups, 183 minutes (range 145-218) in the group treated with fibrin gel and 201 (range 197-231) in the control group (p < 0.001). A negative surgical margin was reported in 18 patients (94.7%) in the group treated with fibrin gel and in 21 patients (100%) in the control group. No difference in renal function was found between the two groups.. Sutureless LPN with fibrin gel can reduce warm ischemia and total operative time while preserving kidney function.

Topics: Aged; Female; Fibrin; Follow-Up Studies; Gels; Humans; Ischemia; Kidney Function Tests; Kidney Neoplasms; Laparoscopy; Length of Stay; Male; Middle Aged; Nephrectomy; Operative Time; Organ Sparing Treatments; Postoperative Complications; Retrospective Studies; Sutureless Surgical Procedures; Warm Ischemia

Sustained, local, low dose growth factor stimulus of target tissues/cells is believed to be of imminent importance in tissue regeneration and engineering. Recently, a technology was developed to bind growth factors to a fibrin matrix using the transglutaminase (TG) activity of factor XIIIa, thus allowing prolonged release through enzymatic cleavage. In this study we aimed to determine whether TG-PDGF.AB in fibrin could improve tissue regeneration in a standard ischemic flap model. In vitro determination of binding and release kinetics of TG-PDGF.AB allowed proof of concept of the developed binding technology. A single spray application of TG-PDGF.AB in fibrin matrix at a concentration of 10 and 100ng/ml significantly reduced ischemia-induced flap tissue necrosis in vivo on day 7 after ischemic impact compared to controls. TG-PDGF.AB at a concentration of 100ng/ml fibrin induced distinct angiogenesis as reflected by significantly improved tissue perfusion assessed by laser Doppler imaging as well as enhanced von Willebrand factor (vWF) protein expression determined by immunohistochemical means. In addition, significantly more mature microvessels were observed with 100ng/ml TG-PDGF.AB in fibrin compared to control and vehicle groups as evidenced by an improved smooth muscle actin (sma)/vWF protein ratio. In conclusion, PDGF.AB in a conjugated fibrin matrix effectively reduced ischemia-induced tissue necrosis, increased tissue perfusion and induced the growth of a mature and functional neovasculature. The sealing properties of the fibrin matrix in conjunction with the prolonged growth factor stimulus enabled by the TG-hook binding technology may present an innovative and suitable tool in tissue regeneration.. In our experimental study we elucidated recombinant platelet derived growth factor (PDGF) as a potential candidate in inducing angiogenesis. To avoid preterm growth factor degradation in vivo PDGF.AB was covalently linked to a fibrin scaffold using a bi-domain functionalized peptide (FXIII substrate site and plasmin cleavage site). This allowed PDGF binding to fibrin during spray application to the donor site and subsequent prolonged release via endogenous plasmin. This resulted in a mature vascular network thus enhancing tissue perfusion and consequently improved clinical outcome. With our present work we could certainly provide researchers and clinicians with an innovative versatile and reproducible technology not only to induce functional vascularity but also to improve attempts in tissue engineering in general by e.g. using different growth factors. Hence, we believe that this approach studied in the present work may provide a valuable input in an effort to drive the aim forward bringing experimental work in tissue engineering to clinic by using a clinically well characterized and used fibrin scaffold in combination with a human recombinant growth factor (fibrin scaffold linked with the specific binding technology).

Topics: Animals; Delayed-Action Preparations; Fibrin; Humans; Ischemia; Neovascularization, Physiologic; Platelet-Derived Growth Factor; Rats; Rats, Sprague-Dawley

The intent of the current study was to investigate the therapeutic contribution of MSCs to vascular regeneration and functional recovery of ischemic tissue. We used a rodent hind limb ischemia model and intramuscularly delivered MSCs within a PEGylated fibrin gel matrix. Within this model, we demonstrated that MSC therapy, when delivered in PEGylated fibrin, results in significantly higher mature blood vessel formation, which allows for greater functional recovery of skeletal muscle tissue as assessed using force production measurements. We observed initial signs of vascular repair at early time points when MSCs were delivered without PEGylated fibrin, but this did not persist or lead to recovery of the tissue in the long-term. Furthermore, animals which were treated with PEGylated fibrin alone exhibited a greater number of mature blood vessels, but they did not arterialize and did not show improvements in force production. These results demonstrate that revascularization of ischemic tissue may be a necessary but not sufficient step to complete functional repair of the injured tissue. This work has implications on stem cell therapies for ischemic diseases and also potentially on how such therapies are evaluated.

Topics: Animals; Biocompatible Materials; Cells, Cultured; Fibrin; Gels; Hindlimb; Ischemia; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Neovascularization, Physiologic; Polyethylene Glycols; Rats; Rats, Inbred Lew; Tissue Scaffolds

We developed an in vivo vascularization model in which human endothelial colony-forming cells (ECFCs) and human mesenchymal progenitor cells (MPCs) form blood vessel networks when co-injected (ECFC + MPC) into nude mice in rat tail type I collagen, bovine fibrin or synthetic peptide PuraMatrix matrices. We used three approaches to determine the onset of functional vascularization when ECFC + MPC suspended in these matrices were implanted in vivo. The first was immunohistochemistry to detect vessels lined by human endothelial cells and filled with red blood cells. The second was in vivo vascular staining by tail vein injection of a mixture of Ulex europaeus agglutinin I (UEA-I), a lectin specific for human endothelium, and Griffonia simplicifolia isolectin B4 (GS-IB4 ), a lectin specific for rodent endothelium. The third approach employed contrast-enhanced ultrasound to measure the perfusion volumes of implants in individual animals over time. Human endothelial-lined tubular structures were detected in vivo on days 1 and 2 after implantation, with perfused human vessels detected on days 3 and 4. Contrast-enhanced ultrasound revealed significant perfusion of ECFC + MPC/collagen implants on days 1-4, at up to 14% perfused vascular volume. ECFC + MPC implanted in fibrin and PuraMatrix matrices also supported perfusion at day 1, as assessed by ultrasound (at 12% and 23% perfused vascular volume, respectively). This model demonstrates that ECFC + MPC suspended in any of the three matrices initiated a rapid onset of vascularization. We propose that ECFC + MPC delivered in vivo provide a means to achieve rapid perfusion of tissue-engineered organs or for in situ tissue repair.

Topics: Animals; Blood Vessels; Capillaries; Cattle; Cell Proliferation; Collagen Type I; Contrast Media; Endothelial Cells; Fibrin; Humans; Ischemia; Lectins; Mesenchymal Stem Cells; Mice; Mice, Nude; Peptides; Perfusion; Rats; Stem Cells; Tissue Engineering

The sprouting of endothelial cells from pre-existing blood vessels represents a critical event in the angiogenesis cascade. However, only a fraction of cultured or transplanted endothelial cells form new vessels. Moreover, it is unclear whether this results from a stochastic process or instead relates to certain endothelial cells having a greater angiogenic potential. This study investigated whether there exists a sub-population of cultured endothelial cells with enhanced angiogenic potency in vitro and in vivo. First, endothelial cells that participated in sprouting, and non-sprouting cells, were separately isolated from a 3D fibrin gel sprouting assay. Interestingly, the sprouting cells, when placed back into the same assay, displayed a sevenfold increase in the number of sprouts, as compared to control cells. Angiotensin-converting enzyme (CD143) was significantly down regulated on sprouting cells, as compared to regular endothelial cells. A subset of endothelial cells with low CD143 expression was then prospectively isolated from an endothelial cell culture. Finally, these cells were found to have greater potency in alleviating local ischemia, and restoring regional blood perfusion when transplanted into ischemic hindlimbs, as compared to unsorted endothelial cells. In summary, this study indicates that low expression of CD143 can be used as a biomarker to identify an endothelial cell sub-population that is more capable to drive neovascularization.

Topics: Animals; Endothelial Cells; Female; Fibrin; Flow Cytometry; Genotype; Hindlimb; Humans; Ischemia; Mice, SCID; Neovascularization, Physiologic; Peptidyl-Dipeptidase A

Clinical trials of therapeutic angiogenesis by vascular endothelial growth factor (VEGF) gene delivery failed to show efficacy. Major challenges include the need to precisely control in vivo distribution of growth factor dose and duration of expression. Recombinant VEGF protein delivery could overcome these issues, but rapid in vivo clearance prevents the stabilization of induced angiogenesis. Here, we developed an optimized fibrin platform for controlled delivery of recombinant VEGF, to robustly induce normal, stable, and functional angiogenesis. Murine VEGF164 was fused to a sequence derived from α2-plasmin inhibitor (α2-PI1-8) that is a substrate for the coagulation factor fXIIIa, to allow its covalent cross-linking into fibrin hydrogels and release only by enzymatic cleavage. An α2-PI1-8-fused variant of the fibrinolysis inhibitor aprotinin was used to control the hydrogel degradation rate, which determines both the duration and effective dose of factor release. An optimized aprotinin-α2-PI1-8 concentration ensured ideal degradation over 4 wk. Under these conditions, fibrin-α2-PI1-8-VEGF164 allowed exquisitely dose-dependent angiogenesis: concentrations ≥25 μg/mL caused widespread aberrant vascular structures, but a 500-fold concentration range (0.01-5.0 μg/mL) induced exclusively normal, mature, nonleaky, and perfused capillaries, which were stable after 3 mo. Optimized delivery of fibrin-α2-PI1-8-VEGF164 was therapeutically effective both in ischemic hind limb and wound-healing models, significantly improving angiogenesis, tissue perfusion, and healing rate. In conclusion, this optimized platform ensured (i) controlled and highly tunable delivery of VEGF protein in ischemic tissue and (ii) stable and functional angiogenesis without introducing genetic material and with a limited and controllable duration of treatment. These findings suggest a strategy to improve safety and efficacy of therapeutic angiogenesis.

Topics: Animals; Female; Fibrin; Gels; Gene Transfer Techniques; Genetic Therapy; Hindlimb; Human Umbilical Vein Endothelial Cells; Humans; Ischemia; Mice; Mice, Inbred Strains; Mice, SCID; Muscle, Skeletal; Neovascularization, Physiologic; Recombinant Proteins; Vascular Endothelial Growth Factor A

G-CSF and EPO have shown a notable capability in neovascularization. However, their use is limited because of untoward leucocytosis, erythrogenesis, and short half-life in the plasma. Herein, we examined whether G-CSF and EPO released from fibrin gel injected into ischemic tissues would synergistically promote neovascularization with limited systematic effects in a rat hindlimb ischemic model.. In vivo study, group Gel received an intramuscular injection of fibrin gel; group Gel+G-CSF received fibrin gel containing human G-CSF; group Gel+EPO received fibrin gel containing human EPO; group Gel+G-CSF&EPO received fibrin gel containing G-CSF and EPO; group G-CSF&EPO received G-CSF and EPO. Through promoting the expression of SDF-1, local high concentration of EPO could traffic CXCR4+ cells mobilized by G-CSF to enhance neovascularization in ischemic muscle. The treatment with Gel+G-CSF&EPO was superior to the other treatments on blood flow reperfusion, capillary density, and α smooth muscle actin-positive vessel density. And this treatment induced a modest WBC count increase in peripheral blood.. G-CSF and EPO released from fibrin gel had a combined effect on postischemia neovascularization. This treatment may be a novel therapeutic modality for ischemic peripheral artery disease.

Topics: Animals; Chemokine CXCL12; Drug Therapy, Combination; Erythropoietin; Fibrin; Gels; Gene Expression Regulation; Granulocyte Colony-Stimulating Factor; Hindlimb; Humans; Ischemia; Male; Neovascularization, Physiologic; Peripheral Arterial Disease; Rats; Rats, Sprague-Dawley

Neo-vessel formation in ischemic tissues relies on numerous growth factors and cell fractions for the formation of mature, stable, functional vasculature. However, the efforts to regenerate tissues typically rely on the administration of a single growth factor or cells alone. Conversely, polymeric matrices have been investigated extensively to deliver multiple growth factors at pre-determined rates to form stable blood vessels in ischemic tissues. We report on a novel sequential delivery system of a fibrin hydrogel containing ionic-albumin microspheres that allows for the controlled release of two growth factors. The use of this system was investigated in the context of therapeutic angiogenesis. Material properties were determined based on degree of swelling measurements and degradation characteristics. Release kinetics of model angiogenic polypeptides FGF-2 and G-CSF were determined using ELISA and the bioactivity of released protein was evaluated in human endothelial cell cultures. The release of growth factors from ionic-albumin microspheres was significantly delayed compared to the growth factor released from fibrin matrices in the absence of spheres. The scaffolds were implanted in a murine critical limb ischemia model at two concentrations, 40 ng (low) and 400 ng (high), restoring 92% of the blood flow in a normally perfused limb using a fibrin hydrogel releasing FGF-2 containing albumin-PLL microspheres releasing G-CSF (measured by LDPI at the high concentration), a 3.2-fold increase compared to untreated limbs. The extent of neo-vessel formation was delineated by immunohistochemical staining for capillary density (CD-31+) and mature vessel formation (α-SMA+). In conclusion, our study demonstrated that the release kinetics from our scaffold have distinct kinetics previously unpublished and the delivery of these factors resulted in hindlimb reperfusion, and robust capillary and mature vessel formation after 8 weeks compared to either growth factor alone or bolus administration of growth factor.

Topics: Actins; Animals; Capillaries; Delayed-Action Preparations; Drug Carriers; Fibrin; Fibroblast Growth Factor 2; Granulocyte Colony-Stimulating Factor; Hindlimb; Human Umbilical Vein Endothelial Cells; Humans; Hydrogels; Ischemia; Kinetics; Mice; Mice, Inbred BALB C; Microspheres; Neovascularization, Physiologic; Perfusion Imaging; Platelet Endothelial Cell Adhesion Molecule-1; Regional Blood Flow; Serum Albumin, Bovine

Topics: Abdominal Fat; Angiogenic Proteins; Animals; Cell Differentiation; Cell Proliferation; Cells, Cultured; Epigastric Arteries; Fibrin; Gene Expression; Inflammation Mediators; Ischemia; Male; Microvessels; Rats; Rats, Inbred Lew; Reperfusion Injury; Stem Cell Transplantation; Stem Cells; Surgical Flaps; Tissue Scaffolds

Transplantation of cord blood-derived mesenchymal stem cells (CBMSCs) into ischemic regions could be a potential therapy for the treatment of ischemic disease, but its efficacy is limited by poor cell survival. We hypothesized that local delivery of fibroblast growth factor 2 (FGF2) to the site of CBMSC transplantation would enhance the viability of CBMSCs transplanted to ischemic tissues. Human CBMSCs were loaded onto fibrin gel with or without FGF2 and transplanted intramuscularly into either normal or ischemic hindlimbs of athymic mice. CBMSC transplantation combined with FGF2 delivery resulted in significantly lower apoptosis and higher survival of transplanted CBMSCs. The enhanced cell survival could be due to the local delivery of FGF2 and the enhanced secretion of anti-apoptotic factor. CBMSC transplantation and FGF2 delivery enhanced the expression of host-derived, platelet-derived growth factor-β and NG2, which induce endothelial cell homing and pericyte recruitment, respectively, and more effectively protected muscles from ischemic degeneration when compared to CBMSC transplantation alone. FGF2 delivery to the site of CBMSC transplantation can enhance the survival of CBMSCs transplanted into ischemic tissues. This approach could be used to improve the angiogenic efficacy of CBMSC transplantation therapy for ischemic disease.

Topics: Animals; Apoptosis; Female; Fetal Blood; Fibrin; Fibroblast Growth Factor 2; Hindlimb; Humans; Ischemia; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Nude; Neovascularization, Physiologic; Platelet-Derived Growth Factor; Vascular Endothelial Growth Factor A

Hypercoagulable state occurs in patients with acute vascular events. We wondered whether clot structure/function is altered in acute ischemic stroke (AIS), like in acute myocardial infarction.. In 45 consecutive patients with AIS (24M, 21F), aged 67.4+/-10.9 years, and 45 healthy controls matched for age and sex, we investigated plasma fibrin clot structure/function by permeation, turbidity, and efficiency of fibrinolysis.. Compared to controls, AIS patients produced clots that had 30.5% less porous network (p<0.0001), were less susceptible to fibrinolysis (10.8% longer lysis time, p=0.001), were 20.5% more compact (p<0.0001), had 17.1% higher clot mass (p<0.0001), and showed increased (by 10.2%) overall fiber thickness (p<0.0001) with 8% shorter lag phase of fibrin formation (p=0.0002). Maximum rate of D-dimer release from clots was similar. Multiple regression analyses for all subjects (n=90) showed that being a stroke patient (p<0.0001), fibrinogen (p<0.0001) and lipoprotein(a) (p=0.0075) were independent predictors of clot permeability (model R2 0.79). Only fibrinogen (p<0.0001) and lipoprotein(a) (p=0.0026) predicted lysis time. All other fibrin parameters were predicted only by being a stroke patient. Clot compaction was associated with neurological deficit on admission (r=-0.81; p<0.0001) and at discharge (r=-0.69; p<0.0001). Patients with 0 or 1 point in the modified Rankin scale (n=19) had 13.3% higher clot permeability compared to the remainder (p=0.02).. This study is the first to show that AIS is associated with unfavorably altered fibrin clot properties that might correlate with neurological deficit.

Topics: Acute Disease; Aged; Blood Coagulation Tests; Family; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Humans; Intracranial Thrombosis; Ischemia; Male; Middle Aged; Permeability; Stroke; Thrombosis

We investigated the angiogenic bioactivity and therapeutic angiogenic effect of vascular endothelial growth factor (VEGF) administration by the heparin-functionalized nanoparticle-fibrin gel complex. The markedly increased bioactivity was observed by the VEGF-loaded nanoparticle-fibrin gel complex, compared to the VEGF-loaded fibrin gel, the nanoparticle-fibrin gel complex without VEGF, or fibrin gel (control) in terms of the capillary density in a mouse subcutaneous implantation model. Furthermore, the VEGF-loaded nanoparticle-fibrin gel complex significantly enhanced the therapeutic angiogenic effect in a rabbit ischemic hind limb model: the noticeable increase in the recovered calf blood pressure, the angiographic score, and the density of collaterals, as well as the stable maintenance of the organized collaterals, compared to the VEGF-loaded fibrin gel. These results show the enhanced angiogenic potential of VEGF administration by the proposed heparin-functionalized nanoparticle-fibrin gel complex.

Topics: Animals; Blood Vessels; Fibrin; Gels; Heparin; Hindlimb; Ischemia; Male; Mice; Mice, Inbred BALB C; Nanoparticles; Neovascularization, Physiologic; Rabbits; Vascular Endothelial Growth Factor A

Heparin-conjugated fibrin (HCF, a mixture of heparin-conjugated fibrinogen and thrombin) was developed as an injectable carrier for long-term delivery of fibroblast growth factor 2 (FGF2), and the therapeutic potential of the HCF system was investigated by evaluating neovascularization in a mouse hind limb ischemia model. HCF released FGF2 for a much longer period than normal fibrin containing free heparin in vitro. The FGF2 released from HCF was bioactive, as it stimulated growth of human dermal fibroblasts in a serum-depleted medium in vitro. In contrast, FGF2 released from normal fibrin did not induce significant cell growth, probably because of its short-term release. HCF alone, HCF loaded with FGF2, and normal fibrin containing free heparin and FGF2 were implanted into mouse ischemic hind limbs for 4 weeks. Histological analysis, Western blot analysis, and immunohistological analysis revealed that ischemic limbs treated with normal fibrin containing free heparin and FGF2, or treated with HCF only, showed severe muscle fibrosis, inflammation, and a low vasculature density. In contrast, mice treated with FGF2-loaded HCF showed significantly reduced muscle fibrosis and inflammation, and dramatically enhanced neovascularization. FGF2 delivery using HCF could be useful for therapeutic angiogenesis as HCF delivery enhances the therapeutic efficacy of FGF2.

Topics: Angiogenesis Inducing Agents; Animals; Blotting, Western; Female; Fibrin; Fibroblast Growth Factor 2; Heparin; Hindlimb; Humans; Immunohistochemistry; Ischemia; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic

Topics: Animals; Fibrin; Heparin; Ischemia; Nanoparticles; Vascular Endothelial Growth Factor A

The development of a scaffold able to mimic the mechanical properties of elastic tissues and to induce local angiogenesis by controlled release of angiogenic growth factors could be applied in the treatment of several ischemic diseases. For this purpose a composite scaffold made of a poly(ether)urethane-polydimethylsiloxane (PEtU-PDMS) semi-interpenetrating polymeric network (semi-IPN) and fibrin loaded growth factors (GFs), such as VEGF and bFGF, was manufactured using spray, phase-inversion technique. To evaluate the contribution of each scaffold component with respect to tissue response and in particular to blood vessel formation, three different scaffold formulations were developed as follows: 1) bare PEtU-PDMS; 2) PEtU-PDMS/Fibrin; and 3) PEtU-PDMS/Fibrin + GFs. Scaffolds were characterized in vitro respect to their morphology, VEGF and bFGF release kinetics and bioactivity. The induction of in vivo angiogenesis after subcutaneous and ischemic hind limb scaffold implantation in adult Wistar rats was evaluated at 7 and 14 days by immunohistological analysis (IHA), while Laser Doppler Perfusion Imaging (LDPI) was performed in the hind limbs at 0, 3, 7, 10 and 14 days. IHA of subcutaneously implanted samples showed that at 7 and 14 days the PEtU-PDMS/Fibrin + GFs scaffold induced a statistically significant increase in number of capillaries compared to bare PEtU-PDMS scaffold. IHA of ischemic hind limb showed that at 14 days the capillary number induced by PEtU-PDMS/Fibrin + GFs scaffolds was higher than that of PEtU-PDMS/Fibrin scaffolds. Moreover, at both time-points PEtU-PDMS/Fibrin scaffolds induced a significant increase in number of capillaries compared to bare PEtU-PDMS scaffolds. LDPI showed that at 10 and 14 days the ischemic/non-ischemic blood perfusion ratio was significantly greater in the PEtU-PDMS/Fibrin + GFs than in the other scaffolds. In conclusion, this study showed that the semi-IPN composite scaffold acting as a pro-angiogenic GFs delivery system has therapeutic potential for the local treatment of ischemic tissue and wound healing.

Topics: Angiogenesis Inducing Agents; Animals; Delayed-Action Preparations; Dimethylpolysiloxanes; Disease Models, Animal; Fibrin; Fibroblast Growth Factor 2; Hindlimb; Humans; Immunohistochemistry; Ischemia; Kinetics; Microscopy, Electron, Scanning; Neovascularization, Physiologic; Polyurethanes; Rats; Rats, Wistar; Tissue Scaffolds; Vascular Endothelial Growth Factor A

Ischemia-reperfusion injury continues to plague the field of lung transplantation, resulting in suboptimal outcomes. In acute lung injury, processes such as ventilator-induced injury, sepsis, or acute respiratory distress syndrome, extravascular fibrin has been shown to promote lung dysfunction and the acute inflammatory response. This study investigates the role of the fibrinolytic cascade in lung ischemia-reperfusion injury and investigates the interplay between the fibrinolytic system and the inflammatory response.. Mice lacking the plasminogen activator inhibitor-1 gene (PAI-1 knock out, PAI-1 KO; and thus increased lysis of endogenous fibrin) and wild-type mice underwent in situ left lung ischemia and reperfusion. Fibrin content in the lung was evaluated by immunoblotting. Reperfusion injury was assessed by histologic and physiologic parameters. Proinflammatory mediators were measured in bronchoalveolar lavage fluid and plasma using enzyme-linked immunosorbent assays.. Ischemia-reperfusion causes fibrin deposition in murine lungs. Less fibrin was seen in PAI-1 KO mice than in wild-type mice subjected to the same ischemia-reperfusion conditions. By histologic criteria, more evidence of ischemia-reperfusion injury was noted (thickening of the interstium, cellular infiltration in the alveoli) in the wild-type than in PAI-1 KO mice. Physiologic parameters also revealed more ischemia-reperfusion injury in the wild-type than in PAI-1 KO mice. Cytokine and chemokines were elevated more in the wild-type group than the PAI-1 KO group.. Lung ischemia-reperfusion injury triggers fibrin deposition in the murine lungs and fibrin creates a proinflammatory environment. Preventing fibrin deposition may reduce ischemia-reperfusion injury and inflammation. This finding may lead to novel treatment strategies for ischemia-reperfusion.

Topics: Acute Lung Injury; Analysis of Variance; Animals; Blotting, Western; Bronchoalveolar Lavage Fluid; Chemokines; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fibrin; Fibrinolysis; Immunohistochemistry; Inflammation Mediators; Ischemia; Mice; Mice, Inbred C57BL; Mice, Knockout; Plasminogen Activator Inhibitor 1; Probability; Random Allocation; Reperfusion Injury; Sensitivity and Specificity

Tissue-type plasminogen activator (tPA) is an extracellular protease that converts plasminogen into plasmin. For tPA to generate plasmin under biologic conditions, a cofactor must first bring tPA and plasminogen into physical proximity. Fibrin provides this cofactor for tPA-mediated plasmin generation in blood. Despite being naturally devoid of fibrin(ogen), tPA-mediated plasmin formation also occurs in the brain. The fibrin-like cofactor(s) that facilitates plasmin formation in the injured brain has remained unknown. Here we show that protein aggregates formed during neuronal injury provide a macromolecular, nonfibrin cofactor that promotes tPA-mediated plasmin formation and subsequent cell breakdown. The binding of plasminogen and tPA to these protein aggregates occurs via distinct mechanisms. Importantly, nonneuronal cell types also exhibit this cofactor effect upon injury, indicating a general phenomenon. This novel cofactor identified in nonviable cells has ramifications for ischemic stroke where tPA is used clinically and where plasmin activity within the injured brain is unwanted. A means of selectively inhibiting the binding of tPA to nonviable cells while preserving its association with fibrin may be of benefit for the treatment of ischemic stroke.

Topics: Animals; Cell Line; Cells, Cultured; Fibrin; Fibrinolysin; Ischemia; Macromolecular Substances; Male; Mice; Mice, Inbred C57BL; Models, Biological; Neurons; Rats; Stroke; Tissue Plasminogen Activator

Skin flap necrosis is one of the hazards encountered in plastic and reconstructive surgery. Angiogenic agents may be useful for treating it by increasing blood flow. The angiogenic effect of fibrin in vitro has been demonstrated, but little is known about its in vivo effect. Te authors tested the hypothesis that local application of fibrin can improve the survival of ischemic skin flaps.. A cranially based dorsal skin flap (3 x 7 cm) was made in each rat. Fibrin (8 mg suspended in 400 microl of phosphate-buffered saline) was applied to the subcutaneous side of elevated skin flaps in the experimental group (n = 15), and phosphate-buffered saline alone was delivered in the control group (n = 15). Tissue blood flow of the skin flaps was measured four times (before the operation and on days 1, 3, and 7) at 1, 3, and 5 cm distal to the baseline of the skin flap. The survival rate of the skin flaps was measured on day 7 and histologic assessments were performed.. The blood flow change rate at 5 cm in the experimental group was significantly higher than that in the control group on day 7 (60.9 +/- 5.7 percent versus 13.7 +/- 4.8 percent, p < 0.001). The survival rate of skin flaps was also significantly improved in the experimental group (77.0 +/- 2.0 percent) in comparison with the control group (54.7 +/- 2.2 percent, p < 0.01). Histologic analysis showed many more blood vessels in the experimental group in comparison with the control group.. The local application of fibrin could improve the blood flow and survival of ischemic skin flaps.

Topics: Animals; Endothelial Cells; Fibrin; Ischemia; Male; Necrosis; Rats; Rats, Wistar; Regional Blood Flow; Surgical Flaps; Tissue Survival

Controlled long-term delivery of basic fibroblast growth factor (bFGF) could be used as an angiogenesis therapy. In this study, novel heparin-conjugated poly(L-lactide-co-glycolide) (PLGA) nanospheres (HCPNs) were developed for long-term, zero-order delivery of bFGF. HCPNs were prepared by using a coupling reaction between amino-terminated PLGA nanospheres and heparin in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide. The amount of heparin conjugated to the PLGA nanospheres was increased up to 29-fold by using nanospheres made from lower molecular weight PLGA, or star-shaped PLGA, as compared to nanospheres made from higher molecular weight PLGA, or linear PLGA. The release of bFGF from HCPNs was sustained for 3 weeks with no initial burst release. The bFGF release period was increased to more than 4 weeks using a delivery system of HCPNs suspended in fibrin gel. The release was nearly zero order. The rate of bFGF release from HCPNs in fibrin gel was controlled by the fibrinogen concentration in the fibrin gel. As the fibrinogen concentration increased, the bFGF release rate decreased. The bioactivity of bFGF released from HCPNs in fibrin gel was assessed using human umbilical vein endothelial cell (HUVEC) culture. bFGF released from HCPNs in fibrin gel exhibited HUVEC growth for 15 days, similar to that of cultures to which bFGF in free form was added daily, suggesting that the delivery system of HCPNs in fibrin gel can release bFGF in a bioactive form for a long period. The therapeutic potential of bFGF delivery using HCPNs in fibrin gel was investigated in a mouse limb ischemia model. Immunohistological analysis of mouse ischemic limbs indicated that the microvessel density was much higher in the ischemic limbs treated with bFGF delivery using HCPNs in fibrin gel than in the ischemic limbs treated with daily injections of bFGF or with bFGF delivery using fibrin gel. This study shows that a bFGF delivery system using HCPNs in fibrin gel exhibits controllable, long-term, zero-order release of bFGF and potentiates the angiogenic efficacy of bFGF administration.

Topics: Animals; Biocompatible Materials; Drug Delivery Systems; Female; Fibrin; Fibroblast Growth Factor 2; Gels; Heparin; Hindlimb; Ischemia; Lactic Acid; Mice; Mice, Inbred C57BL; Nanotubes; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers

1. Fibrin gel has been used as a carrier of angiogenic molecules to promote neovascularization in animal models of limb ischaemia. However, little is known about the effects of fibrin itself under such pathological conditions. Accordingly, the present study tested the efficacy of fibrin in a rabbit model of acute hindlimb ischaemia. 2. Unilateral ischaemia was induced by resection of the left femoral artery. Seven days after surgery, fibrin particles (FP), which were free of fibrinogen, thrombin and vascular endothelial growth factor, were injected directly into the ischaemic thigh muscles. Twenty-four rabbits were divided into four groups, namely a control group receiving phosphate-buffered saline and three FP-treated groups receiving 5, 10 or 20 mg FP. 3. Collateral vessel development and limb perfusion were assessed by angiography, measuring the calf blood pressure ratio (BPR), thermographic scanning and the histological determination of capillary density. 4. At day 35 post-surgery, the treatment with 5 mg FP produced an augmentation of collateral vessel development (P < 0.01), increased numbers of capillaries (P < 0.05) and improved perfusion manifested by a higher blood flow (P < 0.01) and calf BPR (P < 0.05) compared with controls. Treatment with 10 and 20 mg FP had similar effects to those observed with 5 mg FP. 5. The present study reveals that FP promotes angiogenesis in a rabbit model of hindlimb ischaemia, thus providing a feasible approach to therapeutic angiogenesis in ischaemic diseases.

Topics: Angiogenesis Inducing Agents; Angiography, Digital Subtraction; Animals; Blood Pressure; Fibrin; Hindlimb; Injections, Intramuscular; Ischemia; Male; Muscle, Skeletal; Neovascularization, Physiologic; Rabbits; Regional Blood Flow; Thermography; Tibial Arteries

Basic fibroblast growth factor (bFGF) has been known to stimulate the regeneration of a number of tissues including cartilage, nerve, skin, liver, and blood vessel. Delivery of bFGF for a long period in a controlled manner would enhance stimulative effects. The purpose of the present study is to test the hypothesis that the kinetics of bFGF release from fibrin gels could be controlled with heparin and concentrations of fibrinogen and thrombin. The kinetics of bFGF release from fibrin gels with various concentrations of fibrinogen, thrombin, and heparin was determined. The bioactivity of bFGF released from fibrin gels was assessed using dermal fibroblast cell culture. To examine the therapeutic potential of the bFGF delivery system, bFGF-loaded fibrin gels were injected into mouse ischemic limbs. The addition of heparin to fibrin gels decreased the bFGF release rate. As the thrombin content in fibrin gels increased, the bFGF release rate significantly decreased. Similarly, increased concentration of fibrinogen in fibrin gels decreased the bFGF release rate. Basic FGF released from fibrin gels exhibited significantly higher extents of fibroblast growth than bFGF added in a free form daily into the culture medium, suggesting that the fibrin gels may stabilize the bFGF bioactivity. Immunohistological analysis of mouse ischemic limbs indicated that the microvessel density was much higher in the ischemic limbs treated with injection of bFGF-loaded fibrin gels than in the ischemic limbs with no treatment. This study showed that the rate of bFGF release from fibrin gels can be controlled and that the bFGF delivery system has therapeutic potentials for angiogenesis.

Topics: Angiogenesis Inhibitors; Animals; Anticoagulants; Drug Delivery Systems; Drug Implants; Female; Fibrin; Fibrinogen; Fibroblast Growth Factor 2; Gels; Hemostatics; Heparin; Humans; Ischemia; Kinetics; Male; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Thrombin

Severe allograft dysfunction after heart transplant (HT), without ischemia or evidence of cellular rejection upon endomyocardial biopsy (EMB), is a rare but potentially fatal condition that suggests humoral rejection (HR). Its incidence, and the methods of choice for its diagnosis and management, remain uncertain. We retrospectively studied 445 HT patients (April 1991-December 2003) to determine incidence of HR diagnosed by clinical and conventional histopathological criteria. We used immunofluorescence (IF) techniques to test archived frozen EMB issue for IgM, IgG, C1q, C3, fibrin and C4d. Twelve patients (2.7%) fulfilled the criteria for HR after a mean time post-HT of 21.3 +/- 24.7 months (range: 2-72 months). Patients were treated with high doses of steroids and plasmapheresis, with successful recovery in 11 cases. IF studies using classical markers were mainly negative for the six patients with enough EMB tissue for testing. All six patients showed positivity for C4d during the HR episode but not before or after. Humoral rejection was observed in less than 3% of HT patients. Plasmapheresis treatment was highly effective. Classical IF tests were not useful for diagnosis, but C4d appears to be useful both for confirmation of diagnosis and for monitoring response to treatment.

Topics: Adult; Aged; Antibody Formation; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; Biopsy; Complement C1q; Complement C3; Complement C4b; Female; Fibrin; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunoglobulin G; Immunoglobulin M; Ischemia; Male; Microscopy, Fluorescence; Middle Aged; Myocardium; Peptide Fragments; Plasmapheresis; Retrospective Studies; Steroids; Time Factors; Transplantation, Homologous; Treatment Outcome

The underlying cause of acute functional disorders of the inner ear (sudden hearing loss) is usually not detectable with clinical diagnostic measures. It is assumed that functional disorders of the inner ear are merely symptoms and not a disease entity in itself. In particular regional perfusion disturbances, but also autoimmune phenomena, viral infections and micromechanical disorders of the cochlea are seen as pathogenetic principles in inner ear disturbances. Although numerous effective therapeutic options and prophylactic measures for such diseases as myocardial infarction and stroke are available to cardiovascular medicine, they have so far not been applied to the treatment of inner ear problems. Here there is a promising and wide field of options for such diseases that can be traced back to regional perfusion disorders.

Topics: Blood Component Removal; Cardiovascular Diseases; Combined Modality Therapy; Ear, Inner; Fibrin; Hearing Loss, Sudden; Hemodilution; Humans; Ischemia; Lipoprotein(a); Lipoproteins, LDL; Randomized Controlled Trials as Topic; Risk Factors; Thrombolytic Therapy

The incidence of infection following arterial reconstruction using synthetic graft materials varies from less than 1 to 5%. One of three mechanisms is thought to be responsible: 1. intraoperative contamination, 2. extension from adjacent infected or colonized tissue, or 3. hematogenous or lymphogenous seeding. We present ultrastructural data of a patient with a polymicrobial graft infection due to a prostheto-enteric fistula 16 years after reconstruction of an aortobifemoral graft. The polymer surface showed signs of biodegradation and was completely covered with a layer of plasma proteins. Disrupted fibroblasts on the intersegmental graft surface were surrounded by bundles of collagen. Gram-negative rods and grampositive cocci were embedded in an extracellular EPS matrix. Bacterial culture confirmed growth of Eikenella corrodens, Fusobacterium nucleatum and Peptostreptococcus species. Fibrin and granulation tissue from the neoadventitia started to mark off the inflammatory process. Transmission electron microscopy is a valuable tool for the investigation of alloplastic arterial devices. After 16 years of implantation the graft shows different signs of biodegradation.

Topics: Aorta, Abdominal; Aortic Diseases; Bacteriological Techniques; Biofilms; Blood Vessel Prosthesis; Coated Materials, Biocompatible; Collagen; Fibrin; Gram-Positive Cocci; Gram-Positive Rods; Granulation Tissue; Humans; Intestinal Fistula; Ischemia; Leg; Leriche Syndrome; Male; Microscopy, Electron; Middle Aged; Polyesters; Postoperative Complications; Prosthesis-Related Infections

Little is known about interactions between endogenous anti-inflammatory paradigms and microvascular thrombosis in lung ischemia/reperfusion (I/R) injury. Interleukin (IL)-10 suppresses macrophage activation and down-regulates proinflammatory cytokine production, but there are no available data to suggest a link between IL-10, thrombosis, and fibrinolysis in the setting of I/R. We hypothesized that hypoxia/ischemia triggers IL-10 production, to dampen proinflammatory cytokine and adhesion receptor cascades and to restore vascular patency by fibrinolytic potentiation. Studies were performed in a mouse lung I/R model. IL-10 mRNA levels in lung were increased 43-fold over base line by 1 h of ischemia/2 h of reperfusion, with a corresponding increase in plasma IL-10. Expression was prominently localized in bronchial epithelial cells and mononuclear phagocytes. To study the link between IL-10 and fibrinolysis in vivo, the induction of plasminogen activator inhibitor-1 (PAI-1) was evaluated. Northern analysis demonstrated exaggerated pulmonary PAI-1 expression in IL-10 (-/-) mice after I/R, with a corresponding increase in plasma PAI/tissue-type plasminogen activator activity. In vivo, IL-10 (-/-) mice showed poor postischemic lung function and survival after I/R compared with IL-10 (+/+) mice. Despite a decrease in infiltration of mononuclear phagocytes in I/R lungs of IL-10 (-/-) mice, an increased intravascular pulmonary fibrin deposition was observed by immunohistochemistry and Western blotting, along with increased IL-1 expression. Recombinant IL-10 given to IL-10 (-/-) mice normalized the PAI/tissue-type plasminogen activator ratio, reduced pulmonary vascular fibrin deposition, and rescued mice from lung injury. Since recombinant hirudin (direct thrombin inhibitor) also sufficed to rescue IL-10 (-/-) mice, these data suggest a preeminent role for microvascular thrombosis in I/R lung injury. Ischemia-driven IL-10 expression confers postischemic pulmonary protection by augmenting endogenous fibrinolytic mechanisms.

Topics: Animals; Fibrin; Fibrinolysis; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-10; Ischemia; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Plasminogen Activator Inhibitor 1; Reperfusion Injury; Tissue Plasminogen Activator; Transcription, Genetic

does open surgery for abdominal aortic aneurysm (AAA) influence coagulation?. in 23 patients operated on for AAA, cubital blood was sampled pre-, intra- and postoperatively. Femoral blood was also sampled intraoperatively.. preoperatively, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and soluble fibrin (SF) were elevated in AAA patients. During aortic clamping all parameters increased significantly in cubital blood (p<0.01) as well as in femoral blood (p<0.001) and after aortic declamping F1+2 and TAT increased further. F1+2, TAT and SF were significantly higher in femoral than cubital blood. Postoperatively F1+2 and TAT returned to preoperative values, while SF still had a significantly higher level than preoperatively (p<0.001). Blood loss showed co-variation with F1+2 increase in femoral blood after aortic declamping (p<0.05).. these data indicate that the coagulation system was strongly activated by the occurrence of an AAA. During AAA surgery a further extensive activation was seen. The activity was still high, but on decline, one week postoperatively. Ischaemia and reperfusion of the lower part of the body were the major stimuli for thrombin generation and activity.

Topics: Adult; Aged; Antithrombins; Aortic Aneurysm, Abdominal; Fibrin; Humans; Ischemia; Male; Middle Aged; Peptide Fragments; Protein Precursors; Prothrombin; Reperfusion; Thrombin

Topics: Angiography; Arterial Occlusive Diseases; Collateral Circulation; Endothelial Growth Factors; Fibrin; Humans; Injections, Intramuscular; Ischemia; Leg; Lymphokines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

We investigated the relationships between the angiographic severity of peripheral arterial occlusive disease (PAOD) and haemostasis, fibrinolytic, and rheological variables in 219 patients with symptomatic peripheral arterial occlusive disease (PAOD). White cell count, fibrinogen, cross-linked fibrin degradation products (FDP), von Willebrand factor, and plasminogen activator inhibitor levels were all elevated in comparison with age-matched population controls (all p < 0.0001, Mann-Whitney U test), while fibrinogen (Spearman r = 0.30), von Willebrand factor (r = 0.40), and log (FDP) (r = 0.56), (all p < 0.0001) showed a strong correlation with the angiographic extent of PAOD. Multivariate analysis indicated that log (FDP) was a strong independent predictor of the angiographic severity of PAOD (p < 0.0001), in addition to increasing age (p < 0.0001), presence of tissue sepsis (p < 0.02), prior vascular surgery (p = 0.007), and other vascular pathology (p = 0.007). These results confirm that increases in fibrinogen, von Willebrand factor, plasminogen activator inhibitor and fibrin turnover, are strongly associated with the presence of symptomatic peripheral arterial disease, and suggest that there may be causal link between fibrin turnover, as determined by FDP levels, and the extent of peripheral arterial occlusive disease.

Topics: Age Factors; Aged; Angiography; Arterial Occlusive Diseases; Blood Coagulation Factors; Blood Coagulation Tests; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Hemostasis; Humans; Intermittent Claudication; Ischemia; Leg; Male; Middle Aged; Reference Values; Rheology

Measurement of the fibrinolytic response of the peritoneum to experimental peritonitis and ischaemia.. Controlled study. Academic surgical unit, UK MATERIAL: Male Wistar rats. Peritoneal injuries were caused in four groups of male Wistar rats (n = 35 in each group): (1) control group ("open and close" laparotomy); (2) bacterial peritonitis (mixed faecal flora); (3) chemical peritonitis (10 mg/ml tetracycline) and; (4) ischaemic peritoneum (ligated peritoneal buttons). Peritoneal biopsy specimens were taken from five animals in each group at seven time intervals and plasminogen activating activity (PAA) measured by fibrin plate assay.. Compared with the control group the three peritoneal injuries produced a uniform reduction in PAA during the first 6 and 12 hours: at 6 hours the median PAA was 0.029 IU/cm2 for bacterial peritonitis, 0.021 IU/cm2 for chemical peritonitis, and 0.05 IU/cm2 for ischaemic peritoneum compared with 0.112 IU/cm2 for the control group; p < 0.001, ANOVA. At 12 hours the median PAA was 0.024 IU/cm2 for bacterial peritonitis, < or = 0.014 IU/cm2 for chemical peritonitis, and 0.05 IU/cm2 for ischaemic peritoneum compared with 0.112 IU/cm2 for the control group; p < 0.001, ANOVA. There then followed a rebound peak in all groups, maximal at 4-7 days, before a return to baseline values at two weeks.. Peritoneal fibrinolysis was appreciably inhibited after three different standardised peritoneal injuries. The data support the hypothesis that there is a single pathophysiological mechanism of adhesion formation.

Topics: Animals; Bacterial Infections; Fibrin; Fibrinolysis; Ischemia; Male; Models, Biological; Peritoneum; Peritonitis; Plasminogen; Postoperative Period; Rats; Rats, Wistar; Tetracycline; Time Factors

Alveolar and interstitial fibrin deposition is a prominent pathologic feature in many acute lung injury syndromes. Previous studies have suggested that ischemic lung preservation has a stimulatory effect on donor alveolar macrophages (Mphis) during transplantation. An animal model of lung preservation was developed to examine the hypothesis that ischemia enhances Mphi procoagulant activity (PCA) as a potential mechanism contributing to lung reperfusion injury. Histologic examination of ischemic lungs reperfused ex vivo revealed evidence of alveolar fibrin deposition. Mphis lavaged from lungs stored for at least 8 h at 21 degrees C exhibited increased PCA. The use of factor-deficient human plasma characterized this Mphi procoagulant as tissue factor (TF). Since increased PCA correlated with decreased airspace pO2 at the end of preservation, the effect of various O2 concentrations on PCA induction in vivo and in vitro was examined. Lung inflation during ischemia with decreasing O2 concentrations confirmed that hypoxia was associated with a rise in Mphi PCA in situ. However, in vitro exposure of Mphis to hypoxia did not increase Mphi PCA, suggesting that hypoxia alone was not responsible for induction of this procoagulant effect. Northern blot analysis demonstrated an increase in TF mRNA levels from in situ but not in vitro Mphis, thereby confirming transcriptional TF induction in this group. In addition, enhanced PCA was observed when Mphis were suspended in the bronchoalveolar lavage supernatant from the ischemic lungs stored at 21 degrees C. This suggests that in situ lung ischemia and hypoxia may produce soluble factors that either directly or indirectly stimulate Mphi TF expression. These factors may contribute to Mphi-mediated ischemic lung injury.

Topics: Animals; Blotting, Northern; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Fibrin; Hypoxia; Ischemia; Macrophages, Alveolar; Male; Microscopy, Electron, Scanning; Pulmonary Alveoli; Rats; Rats, Wistar; Reperfusion Injury; RNA, Messenger; Thromboplastin; Tubulin

A case-control comparison within the framework of the prospective, multidisciplinary PLAT Study was performed to assess whether altered baseline fibrinolytic variables were associated with an elevated risk of ischemic thrombotic events in patients with documented coronary, cerebral, and/or peripheral atherosclerotic disease. Fibrinogen, D-dimer, tissue plasminogen activator (t-PA) antigen, and fibrinolytic activity before and after venous stasis (delta = difference between the two values), t-PA inhibitor, and lipid levels in 60 atherosclerotic patients with a thrombotic event during the first year of follow-up were compared with those in 94 atherosclerotic patients without such events, who were matched for age, sex, and diagnosis at enrollment. Events were associated with a higher release of delta t-PA antigen (P = .047), higher D-dimer (P = .024), and higher t-PA inhibitor (P = .001) levels. delta Fibrinolytic activity was correlated inversely with t-PA inhibitor (P < .01) and triglycerides (P < .05). D-Dimer was also correlated with systolic blood pressure (P < .01). Atherosclerotic patients at higher risk of thrombotic ischemic events are characterized by increased fibrin turnover and impaired fibrinolytic activity due to high t-PA inhibitor levels. This hemostatic disequilibrium may participate with conventional risk factors such as elevated triglyceride levels and systolic blood pressure in the multifactorial mechanism of ischemic sequelae in patients with preexisting vascular atherothrombotic disease.

Topics: Aged; Arteriosclerosis; Case-Control Studies; Female; Fibrin; Fibrinolysis; Forecasting; Humans; Ischemia; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Risk Factors

The presence of pericapillary fibrin and complement C3c in the ulcers of 19 patients with venous hypertension and 14 patients with ischaemic leg ulcers was investigated using histochemical and immunohistochemical techniques. There was deposition of fibrin around the capillaries in the central part of the ischaemic ulcers, and the venous hypertension ulcers, and in the non-ulcerated skin around one of the venous hypertension ulcers and two of the ischaemic leg ulcers. The deposition of fibrin is a secondary phenomenon that occurs in the area of ulcerated skin and does not play a major causal role in the formation of chronic leg ulcers.

Topics: Aged; Aged, 80 and over; Capillaries; Complement System Proteins; Female; Fibrin; Humans; Ischemia; Leg; Leg Ulcer; Male; Middle Aged; Venous Pressure

Predictable vascular responses to burn injury can occur where blood vessels are occluded in and just beneath the site of trauma. The loss of vascular patency is linked to the development of ischemia in the surrounding skin. Several mechanisms may be responsible for this occlusion, and their identification will provide a logical means for prevention or reversal of the occlusion. The role of fibrin deposition was investigated here using a rat burn model. If an intravascular fibrin clot is a primary cause of early occlusion, the depletion of circulating fibrinogen should prevent its deposition. Ancrod, a pit viper venom trypsin-like proteinase, when given systemically, converts fibrinogen into a soluble product which does not clot. In studies here, the host is depleted of fibrinogen by intravenous injections of ancrod for 3 days before standard burn trauma. Burn injury in defibrinogenized rats resulted in greatly reduced local vascular occlusion. These results support the idea that vascular occlusion caused by burn injury is dependent on the deposition of fibrin. It is conjectured that the vascular occlusion of burn injury can be reversed by preventing or breaking down intravascular fibrin clots.

Topics: Ancrod; Animals; Arterial Occlusive Diseases; Burns; Fibrin; Ischemia; Male; Models, Cardiovascular; Rats; Rats, Inbred Strains; Skin; Vascular Patency

The correlation between the extent of intrarenal fibrin deposition induced by 15, 20 and 30-min bilateral occlusion of the renal arteries and the reduction of glomerular filtration rate (GFR) has been studied. The tissue level of fibrin was estimated by 125I-labelled human fibrinogen. There was a significant negative correlation between cortical and medullary fibrin content and GFR. In rats pretreatment with the defibrinating agent Arwin failed to prevent postischaemic coagulation in the kidney and the reduction of GFR.

Topics: Ancrod; Animals; Fibrin; Fibrinogen; Fibrinolysis; Glomerular Filtration Rate; Ischemia; Kidney; Ligation; Male; Rats; Renal Artery; Thrombin Time

Topics: Adenosine Diphosphate; Arteriosclerosis; Blood Coagulation Factors; Blood Flow Velocity; Blood Platelets; Connective Tissue; Cyclic AMP; Endothelium; Fibrin; Humans; Ischemia; Platelet Adhesiveness; Platelet Aggregation; Rheology; Thrombosis

In various human and experimental renal failures some hemostatic parameters indicate the occurrence of intrarenal blood coagulation (1, 2). However, the fact that the common anticoagulants fail to cure the acute renal failure (3) appears to suggest either that they are ineffective against the intrarenal blood coagulation or no causal relationship exists between the hemostatic disturbances and impaired renal function. Therefore this study was undertaken to investigate the relationship between coagulation and impairment of renal function after a 45-min ischemic period in untreated, heparin-treated and in heparin- plus antiplatelet serum (APS)-treated thrombocytopenic animals.

Topics: Animals; Blood Coagulation; Blood Platelets; Fibrin; Heparin; Immune Sera; Ischemia; Kidney Cortex; Male; Rats; Rats, Inbred Strains; Renal Circulation; Thrombocytopenia

Placental bed biopsies were performed during caesarean section in a series of 137 patients. Analysis of the morphological findings confirms that vascular physiological changes were reduced in pre-eclampsia and in normotensive intrauterine growth retardation. In pre-eclampsia, acute atherosis in the decidual segments of uteroplacental arteries was a prominent feature. Intimal thickenings of the myometrial segments of the uteromaternal arteries were also noted. Normotensive intrauterine growth retardation cases were characterized by intimal thickenings of the myometrial segments of the uteroplacental arteries. Immunofluorescent investigations have demonstrated that the deep vascular stenoses were not associated with immunoglobulin deposition while in distal arterial segments displaying acute atherosis a positive immunofluorescence for IgG and fibrin and, more irregularly, for C'3 and IgM could be noted. These findings lead us to suggest that an immunological mechanism may be involved in the pathogenesis of acute atherosis.

Topics: Complement C3; Female; Fetal Growth Retardation; Fibrin; Fluorescent Antibody Technique; Humans; Immunoglobulin G; Ischemia; Placenta; Placenta Diseases; Placental Insufficiency; Pre-Eclampsia; Pregnancy

A 48-year-old man with accelerated hypertension developed right-sided ischemic colitis. There was no evidence of another cause of vascular inadequacy. Microscopically, the bowel showed ischemic alterations of different stages. The arterial alterations of different stages. The arterial vessels showed minimal changes. In older lesions, fibrosis was prominent and the mucosa was atrophic. In more recent lesions, some vessels of the submucosa were plugged with fibrin and the overlying mucosa was infiltrated by nonorganized hemorrhage and cellular elements.

Topics: Arteries; Atrophy; Colitis; Colon; Fibrin; Gastrointestinal Hemorrhage; Humans; Hypertension; Intestinal Mucosa; Ischemia; Male; Middle Aged

Twenty cases of ischemic bowel disease were analysed to determine the frequency and significance of fibrin thrombi in this condition. Fibrin thrombi were present in all 10 patients with occlusive ischemic bowel disease and in 7 of the 10 patients with nonocclusive ischemic bowel disease. In addition, fibrin thrombi were noted in a wide variety of specific and nonspecific inflammatory bowel diseases and in acute appendicitis. We conclude that fibrin thrombi are a nonspecific feature of tissue necrosis and that their mere presence in the bowel should not be regarded as an expression of disseminated intravascular coagulation.

Topics: Appendicitis; Colitis, Ulcerative; Crohn Disease; Fibrin; Humans; Intestinal Diseases; Intestinal Obstruction; Intestines; Ischemia; Necrosis; Thrombosis

Five techniques of producing temporary renal ischaemia have been evaluated in the rat. Damage was assessed by measuring inulin clearance, change in renal cortical intracellular water and 125I-fibrin deposition. Continuous renal artery occlusion produces significantly less renal damage than the other techniques commonly used.

Topics: Animals; Fibrin; Inulin; Ischemia; Kidney; Methods; Rats; Renal Artery; Water

Topics: Animals; Blood Viscosity; Clofibrate; Fibrin; Fibrinogen; Humans; Intermittent Claudication; Ischemia; Leg; Rabbits

Carrageenan suppressed antibody responses to SRBC in mice and rats, measured in terms of splenic IgM PFC production. The effect, in mice, was dependent on dose and on the temporal relationship between treatment and antigen administration. Carrageenan was found to alter the time course of the PFC response and also to produce disseminated intravascular coagulation. Some correlation between the observed effects and the use of chemically distinct carrageenans was found. The possible mode of action of carrageenan is discussed in the light of these, and other findings.

Topics: Animals; Antibody Formation; Antibody-Producing Cells; Carrageenan; Depression, Chemical; Disseminated Intravascular Coagulation; Ear, External; Fibrin; Hemolytic Plaque Technique; Immunosuppressive Agents; Ischemia; Liver; Male; Mice; Microcirculation; Rats; Structure-Activity Relationship; Tail; Time Factors

The clinical and renal biopsy findings from two patients in whom renal functional abnormalities developed in the late postpartum period are described. Both biopsies showed fibrin deposition in the renal vasculature, in one case marked and in the other mild. The patient with the more severely damaged kidney subsequently died, and the other is alive but with evidence of slowly progressing renal damage. The clinicopathological spectrum and pathogenesis of late postpartum renal failure are discussed.

Topics: Acute Kidney Injury; Animals; Biopsy; Blood Coagulation; Disseminated Intravascular Coagulation; Ergot Alkaloids; Female; Fibrin; Fluorescent Antibody Technique; Hemolytic-Uremic Syndrome; Humans; Hypertension; Ischemia; Kidney; Kidney Glomerulus; Pregnancy; Puerperal Disorders

The significance and frequency of fibrin thrombi (FT), the pathological hallmark of disseminated intravascular coagulation (DIC), in ischemic intestine were analyzed in a retrospective study of the infarcted bowel of patients with occlusive mesenteric ischemia (OMI) and nonocclusive mesenteric ischemia (NOMI). Representative intestinal sections were studied from 10 patients with NOMI of the small and/or large bowel and 12 patients, with OMI of varied etiology. Three patients with inflammatory bowel disease and 1 patient with DIC and bowel necrosis were also studied. Routine hematoxylin and eosin stains for fibrin were prepared for each specimen. The number of FT was quantitated. FT were identified in each of the 10 cases of NOMI; however in only 2 were they prominent. FT were identified in 6 of the 12 cases of OMI and in 4 of these 6 they were a prominent feature. Rare FT were present in the cases of inflammatory bowel disease and did not correlate with the inflammatory process. No FT were present in the intestinal sections of the DIC case. FT are a nonspecific feature of necrosis and can be identified in both occlusive and nonocclusive ischemic bowel disease. Their presence in the intestine of NOMI therefore cannot be used to implicate DIC as the primary cause of this entity.

Topics: Blood Platelets; Disseminated Intravascular Coagulation; Enteritis; Fibrin; Humans; Infarction; Intestinal Diseases; Intestines; Ischemia; Mesenteric Vascular Occlusion; Mesentery; Necrosis; Retrospective Studies; Thrombosis

Two patients who developed reversible renal failure during intermittent rifampicin therapy are described. Both had febrile reactions to rifampicin. The first was also found to have uraemia associated with swelling of the glomerular endothelial cells. The second developed tubular necrosis unassociated with haemolysis or shock. The pathogenesis of the renal lesion in these two patients, as revealed by light microscopy, immunofluorescence studies and electron microscopy, is discussed.

Topics: Acute Kidney Injury; Adult; Antibodies; Endothelium; Ethambutol; Fever; Fibrin; Humans; Immune Complex Diseases; Ischemia; Kidney Glomerulus; Kidney Tubules; Male; Necrosis; Rifampin; Tuberculosis, Pulmonary; Uremia

The effect of temporary myocardial ischaemia (x 52 mins) and reperfusion (x 23 hrs 8 mins) on myocardial tissue fibrinolysis and 125I fibrinogen incorporation into fibrin was investigated in nine baboons. Fibrinolytic activity was reduced by 54% in the endocardium of the ischaemic reperfused myocardium and the 125I fibrinogen activity was elevated by 480%. The reduction in myocardial fibrinolytic activity following ischaemia and reperfusion may be due to endothelial damage.

Topics: Animals; Coronary Circulation; Endocardium; Fibrin; Fibrinogen; Fibrinolysis; Haplorhini; Ischemia; Myocardial Infarction; Papio

The effects of various combinations of streptokinase-induced hyperfibrinolysis, electric shock, myocardial ischemia, and ventricular fibrillation on cat pericardial and epcardial fibrinolytic activity were studied. Streptokinase alone or electric shock alone slightly increased the periepicardial fibrinolytic activity but epicardial rebleeding did not occur. However, streptokinase infusions followed by electric shock and/or myocardial ischemia and/or ventricular fibrillation significantly incrased the periepicardial fibrinolytic activity and rebleeding of the epicardium occurred. Topical application of the fibrinolytic inhibitor epsilonaminocaproic acid (EACA) prevented the epicardial rebleeding.

Topics: Aminocaproates; Animals; Blood Coagulation; Blood Coagulation Tests; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Cats; Electric Stimulation; Fibrin; Fibrinogen; Fibrinolysis; Heart Diseases; Hemorrhage; Injections, Intravenous; Ischemia; Pericardium; Postoperative Complications; Streptokinase; Ventricular Fibrillation

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Brain; Cerebrovascular Disorders; Cholesterol; Fibrin; Fibrinogen; Fibrinolysis; Humans; Ischemia; Plasminogen; Triglycerides

Topics: Adult; Aged; Blood Platelets; Collagen; Endothelium; Female; Femoral Vein; Fibrin; Fibrinolysis; Hemosiderin; Humans; Ischemia; Leukocytes; Male; Middle Aged; Plasminogen; Popliteal Vein; Staining and Labeling; Thrombophlebitis; Veins

Topics: Acute Kidney Injury; Aminocaproates; Animals; Autoradiography; Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Fibrinolysis; Fluorescent Antibody Technique; Glycerol; Half-Life; Hemoglobins; Hemoglobinuria; Iodine Isotopes; Ischemia; Kidney; Kidney Cortex Necrosis; Kidney Glomerulus; Kidney Tubules; Rabbits; Rats; Serum Albumin, Radio-Iodinated; Sympathectomy

Topics: Adult; Autopsy; Basement Membrane; Biopsy; Biopsy, Needle; Epithelium; Female; Fibrin; Graft Rejection; Humans; Ischemia; Kidney; Kidney Cortex; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Male; Microscopy, Electron; Necrosis; Thrombosis; Transplantation, Homologous

Topics: Autopsy; Basal Ganglia; Brain; Disseminated Intravascular Coagulation; Female; Fetal Diseases; Fibrin; Humans; Hydrocephalus; Infant, Newborn; Ischemia; Male; Necrosis; Placenta; Placenta Diseases; Plasma Cells; Pregnancy; Thrombosis; Virus Diseases

Topics: Acute Kidney Injury; Basement Membrane; Blood Coagulation Disorders; Diabetic Nephropathies; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Fibrinolysis; Glomerulonephritis; Hemagglutination Tests; Hemolytic-Uremic Syndrome; Humans; Ischemia; Kidney; Kidney Diseases; Male; Middle Aged; Pre-Eclampsia; Pregnancy; Thrombosis; Urokinase-Type Plasminogen Activator

Topics: Appendectomy; Autopsy; Cachexia; Chemical Precipitation; Fibrin; Humans; Intracranial Pressure; Ischemia; Lymphatic System; Sepsis; Shwartzman Phenomenon; Spleen

Topics: Animals; Dog Diseases; Dogs; Fibrin; Intervertebral Disc Displacement; Ischemia; Necrosis; Spinal Cord; Syndrome

Topics: Acute Kidney Injury; Angiography; Animals; Antibodies; Antigen-Antibody Reactions; Blood Coagulation; Complement System Proteins; Dextrans; Dogs; Fibrin; Glomerular Filtration Rate; Histamine H1 Antagonists; Immunosuppression Therapy; Ischemia; Kidney; Kidney Transplantation; Oxygen Consumption; Sodium; Transplantation Immunology; Transplantation, Homologous; Vasoconstrictor Agents

The coagulation and fibrinolytic mechanisms were investigated in a group of patients with severe pre-eclampsia and eclampsia and the findings were compared with those of healthy women in late pregnancy. In patients with pre-eclampsia the following significant differences were found: (1) greater depression of plasma fibrinolytic activity (euglobulin lysis time) than in normal pregnancy, (2) a higher level of inhibitor to urokinaseinduced lysis, (3) increased levels of serum fibrin degradation products, and (4) reduced platelet counts.In patients with eclampsia a progressive increase of the level of serum fibrin degradation products was found over the three days following eclamptic seizures. No such increase occurred after grand mal seizures in late pregnancy. The findings in this study support the view that intravascular clotting is taking place in pre-eclampsia and that this disturbance of the balance between coagulation and fibrinolysis may be localized to certain areas of the vascular compartment, particularly the placental and renal circulations. Fibrin deposition in the maternal vessels supplying the placenta would impair the placental blood flow, which may explain the placental insufficiency which occurs in pre-eclampsia. Likewise fibrin deposition in the renal vasculature will result in glomerular damage and proteinuria. Hypertension may be related to the renal ischaemic changes or a compensatory response to the presence of fibrin deposition in the vascular compartment. This evidence of intravascular fibrin deposition raises the question of the possible therapeutic value of antithrombotic agents to inhibit the clotting process. On a theoretical basis such treatment might be expected to improve blood flow to the placenta and thereby fetal growth.

Topics: Adult; Blood Coagulation; Blood Platelets; Eclampsia; Embryonic and Fetal Development; Epilepsy, Tonic-Clonic; Female; Fibrin; Fibrinolysis; Fibrinolytic Agents; Humans; Hypertension; Ischemia; Kidney; Kidney Diseases; Maternal-Fetal Exchange; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Serum Globulins

Topics: Arteriosclerosis; Arteriosclerosis Obliterans; Blood Vessels; Collagen; Connective Tissue; Diabetic Angiopathies; Elastic Tissue; Embolism; Endarteritis; Fibrin; Humans; Hyalin; Ischemia; Necrosis; Vasa Vasorum

Topics: Animals; Fibrin; Fibrinogen; Fibrinolysis; Fluorescent Antibody Technique; Glomerular Filtration Rate; Histocompatibility; Humans; Immune Sera; Immunoassay; Immunoelectrophoresis; Ischemia; Kidney; Kidney Transplantation; Macromolecular Substances; Prednisone; Proteinuria; Rabbits; Time Factors; Transplantation Immunology; Transplantation, Homologous

Topics: Animals; Constriction; Dogs; Fibrin; Hypersplenism; Ischemia; Regional Blood Flow; Spleen; Splenic Artery; Splenic Vein; Splenomegaly