fibrin and Scleroderma--Systemic

Coagulation factor XIII (FXIII), a plasma transglutaminase, is best known as the final enzyme in the coagulation cascade, where it is responsible for cross-linking of fibrin. However, a growing body of evidence has demonstrated that FXIII targets a wide range of additional substrates that have important roles in health and disease. These include antifibrinolytic proteins, with cross-linking of α2-antiplasmin to fibrin, and potentially fibrinogen, being the principal mechanism(s) whereby plasmin-mediated clot degradation is minimised. FXIII also acts on endothelial cell VEGFR-2 and αvβ3 integrin, which ultimately leads to downregulation of the antiangiogenic protein thrombospondin-1, promoting angiogenesis and neovascularisation. Under infectious disease conditions, FXIII cross-links bacterial surface proteins to fibrinogen, resulting in immobilisation and killing, while during wound healing, FXIII induces cross-linking of the provisional matrix. The latter process has been shown to influence the interaction of leukocytes with the provisional extracellular matrix and promote wound healing. Through these actions, there are good rationales for evaluating the therapeutic potential of FXIII in diseases in which tissue repair is dysregulated or perturbed, including systemic sclerosis (scleroderma), invasive bacterial infections, and tissue repair, for instance healing of venous leg ulcers or myocardial injuries. Adequate levels of FXIII are also required in patients undergoing surgery to prevent or treat perioperative bleeding, and its augmentation in patients with/at risk for perioperative bleeding may also have potential clinical benefit. While there are preclinical and/or clinical data to support the use of FXIII in a range of settings, further clinical evaluation in these underexplored applications is warranted.

Topics: Angiogenesis Inducing Agents; Animals; Bacterial Infections; Blood Coagulation; Blood Loss, Surgical; Coagulants; Factor XIII; Factor XIII Deficiency; Factor XIIIa; Fibrin; Humans; Neovascularization, Physiologic; Postoperative Hemorrhage; Scleroderma, Systemic; Signal Transduction; Substrate Specificity; Thrombospondin 1; Wound Healing

Topics: Animals; Arterioles; Capillaries; Child; Fibrin; Humans; Raynaud Disease; Scleroderma, Systemic; Serotonin; Skin

To assess thrombin generation, fibrin formation, and structure together with the fibrinolytic status in patients with systemic sclerosis (SSc) in relation to the occurrence of digital ulcers (DUs) during the course of disease.. We studied variables of endothelial dysfunction, thrombin generation, overall hemostatic potential, and fibrin clot turbidity in plasma from 58 patients with SSc (39 with DU history and 19 DU-naïve) and 46 matched healthy controls (HCs). Fibrin structure was visualized using scanning electron microscopy (SEM). Finally, 39 patients with a history of DUs were followed for 1.5 years and the predictive value of all investigated markers for new DU onset was explored.. Significantly enhanced endogenous thrombin potential (ETP) and prolonged clot lysis time (CLT) were found in patients with DUs compared to HCs. CLT was prolonged in patients with DUs compared to those without, showing good validity in identifying DUs with an area under the curve of 0.7 (95% CI 0.6-0.8). The levels of ETP and intercellular adhesion molecule 1 were independently associated with CLT. Over the follow-up period, 20 patients developed new DUs. CLT was prolonged (. Our results suggest that impaired fibrinolysis might have an emerging role in underlying digital vasculopathy and its progression in SSc.

Topics: Fibrin; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Scleroderma, Systemic; Skin Ulcer; Thrombin; Thrombosis; Ulcer

Topics: Female; Fibrin; Humans; Middle Aged; Platelet-Rich Plasma; Scleroderma, Systemic; Skin Ulcer; Toes; Treatment Outcome; Wound Healing

In systemic sclerosis (SSc), chronic and uncontrolled overexpression of vascular endothelial growth factor (VEGF) results in chaotic vessels, and intractable fingertip ulcers. Vice versa, VEGF is a potent mediator of angiogenesis if temporally and spatially controlled. We have addressed this therapeutic dilemma in SSc by a novel approach using a VEGF121 variant that covalently binds to fibrin and gets released on demand by cellular enzymatic activity. Using University of California at Davis (UCD)-206 chickens, we tested the hypothesis that cell-demanded release of fibrin-bound VEGF121 leads to the formation of stable blood vessels, and clinical improvement of ischaemic lesions.. Ninety-one early and late ischaemic comb and neck skin lesions of UCD-206 chickens were treated locally with VEGF121-fibrin, fibrin alone, or left untreated. After 1 week of treatment the clinical outcome was assessed. Angiogenesis was studied by immunofluorescence staining of vascular markers quantitatively analysed using TissueQuest.. Overall, 79.3% of the lesions treated with VEGF121-fibrin showed clinical improvement, whereas 71.0% of fibrin treated controls, and 93.1% of untreated lesions deteriorated. This was accompanied by significantly increased growth of stable microvessels, upregulation of the proangiogenic VEGFR-2 and its regulator TAL-1, and increase of endogenous endothelial VEGF expression.. Our findings in the avian model of SSc suggest that cell-demanded release of VEGF121 from fibrin matrix induces controlled angiogenesis by differential regulation of VEGFR-1 and VEGFR-2 expression, shifting the balance towards the proangiogenic VEGFR-2. The study shows the potential of covalently conjugated VEGF-fibrin matrices for the therapy of ischaemic lesions such as fingertip ulcers.

Topics: Animals; Chickens; Disease Models, Animal; Fibrin; Neovascularization, Pathologic; Scleroderma, Systemic; Skin Ulcer; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors

Scleroderma renal crisis (SRC) can lead to end-stage renal disease (ESRD) and subsequent need for dialysis and/or renal transplantation. We review all reported cases of renal transplantations in scleroderma patients from PubMed search, present UNOS data on transplant outcomes, and identify predictors for allograft SRC. Of the five cases with recurrent SRC, all developed ESRD within a year of onset of native kidney SRC, whereas none of those who developed ESRD more than 1-2 years after the onset of SRC developed recurrence. Anemia preceded allograft SRC in two cases, pericardial effusion in one, and skin tightening in two others. UNOS data (October 1987-July 2004) documented 260 transplants performed for the renal diagnosis of scleroderma, with a 5-year graft survival rate of 56.7%. The risk for allograft SRC recurrence appears to correlate with early native renal function loss following the onset of SRC. Recurrent SRC in the allograft may be heralded by multiple clinical markers known to be predictive of severe scleroderma, including progression of diffuse skin thickening, new-onset anemia and cardiac complications.

Topics: Anemia; Arterioles; Autoimmune Diseases; Disease Progression; Edema; Female; Fibrin; Graft Rejection; Graft Survival; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Transplantation; Kidney Tubules; Leukocytes, Mononuclear; Lymphocytes; Middle Aged; Pericardial Effusion; PubMed; Recurrence; Renal Dialysis; Risk Factors; Scleroderma, Systemic; Skin; Thrombosis; Time Factors; Transplantation, Homologous

Although abnormalities of alveolar fibrin turnover have been reported to play a role in the development of idiopathic pulmonary fibrosis (IPF), the pathophysiological relevance remains unclear. We therefore investigated the localization of tissue factor (TF) and fibrin deposition in patients with IPF using immunohistochemistry and compared the results with those from patients who had interstitial pneumonia associated with systemic sclerosis (IP-SSc) and idiopathic bronchiolitis obliterans with organizing pneumonia (BOOP). Expression of TF-mRNA was also assessed, using in situ hybridization with a digoxigenin-labeled cRNA probe. In patients with IPF, IP-SSc, and idiopathic BOOP, the TF antigen was positively stained in type II pneumocytes and in some alveolar macrophages. The fibrin antigen was stained in the type II pneumocytes and the adjacent area. Tissue factor-mRNA was expressed in the type II pneumocytes and in some alveolar macrophages. Neither TF antigens nor TF-mRNA were detected in the normal lung. These results indicate that type II pneumocytes are a major source of TF, suggesting that TF production in these cells is closely related to fibrin deposition in the lungs of people with these diseases.

Topics: Base Sequence; Biopsy; Cryptogenic Organizing Pneumonia; DNA Primers; Fibrin; Humans; Immunohistochemistry; In Situ Hybridization; Lung; Lung Neoplasms; Molecular Sequence Data; Polymerase Chain Reaction; Pulmonary Fibrosis; RNA, Messenger; Scleroderma, Systemic; Thromboplastin

Systemic sclerosis (SSc) is a disease characterized by progressive microvascular occlusion and fibrosis resulting in irreversible organ damage, the pathogenesis of which is felt to be of vascular origin. To gain a comprehensive view of the coagulation/fibrinolytic balance in SSc, a number of haemostatic and fibrinolytic variables were measured in 26 SSc patients (11 limited, 15 diffuse) and in 22 control subjects. Of the coagulation activation markers, the mean plasma level of prothrombin fragment 1 + 2 (F1 + 2), but not of thrombin-antithrombin complexes (TAT), was higher in SSc patients than in controls (P < 0.001). Plasma levels of fibrin split product D-dimer (DD), fibrinogen (FNG) and von Willebrand factor (vWF) were higher amongst patients than controls (P < 0.001). vWF and FNG levels were positively correlated (P < 0.001). Mean levels of DD and vWF were more elevated in patients with diffuse than limited disease (P = 0.001 and P = 0.04, respectively). On the fibrinolytic side, defective tissue plasminogen activator (tPA) release (venous occlusion test, stimulated level < basal level) was noted in 46% (12/26) of SSc patients, but only in 4% (1/22) of controls. Patients had higher mean levels of tPA inhibitor (PAI) than controls (P < 0.001), levels being more elevated amongst patients with diffuse than limited disease (P = 0.01). An abnormally high lipoprotein (a) [Lp(a)] level was found in 9% (2/20) of control subjects, but in 30% (8/26) of SSc patients (P = 0.04) where it clustered with fibrinolytic defects. Altogether, these data suggest that patients with SSc are in a hypercoagulable state characterized by elevated plasma levels of FNG and vWF, by a dual hypofibrinolytic pattern (defective tPA release and elevated PAI), and by increased thrombin generation with enhanced fibrin formation. Higher levels of vWF, DD and PAI in patients with diffuse disease are consistent with more extensive (micro)vascular involvement, although no causal relationship can be inferred. The lack of a parallel increase of TAT with F1 + 2, in the presence of normal levels of antithrombin III (ATIII), indirectly suggests an impairment of the heparan sulphate-ATIII system which would favour thrombin generation. Since thrombin may act as a mitogen for fibroblasts, may upregulate vWF, PAI and endothelin production by endothelial cells, and may promote fibrin deposition on the vessel wall leading to worsening of microvascular occlusions, limitation of thrombin generation, besi

Topics: Adult; Antithrombin III; Blood Coagulation; Endothelins; Female; Fibrin; Fibrinogen; Fibrinolysis; Humans; Lipoprotein(a); Male; Middle Aged; Prothrombin; Scleroderma, Systemic; Syndrome; Thrombin; Tissue Plasminogen Activator; von Willebrand Factor

Abnormalities of tissue type plasminogen activator (tPA) and plasminogen activator inhibitor have been described in some patients with systemic sclerosis (SSc). We studied 128 unselected SSc sera for the presence of autoantibodies to fibrin bound tPA.. A solid phase fibrin-tPA immunoassay utilized 500 IU/ml tPA bound to solid phase fibrin. Sera diluted 1/50 were incubated with the fibrin bound tPA, the plates were washed, and bound immunoglobulins were detected using polyvalent peroxidase labelled goat antihuman immunoglobulins. Controls included plates coated with fibrin alone or tPA passively adsorbed to the plastic. Sera were considered positive when the A490/630 was above the mean + 2 SD (> 0.055) obtained with normal human serum in 2 independent tests.. 25/128 (20%) SSc sera demonstrated antibody reactivity with fibrin bound tPA (mean A490/630 = 0.112). Detailed clinical data were available on 117/128 patients with SSc and on 21/25 anti-tPA positive patients. The mean age of the anti-tPA positive group was 51 yrs and of the anti-tPA negative group 49.6 yrs. Within the anti-tPA positive group there was a significantly higher proportion (p > 0.05) of patients with the CREST (calcinosis, Raynaud's esophageal dysmotility, sclerodactyly, telangiectasias) variant of SSc (7/25 = 28% vs 11/103 = 11%) and pulmonary hypertension (5/21 = 24% vs 6/96 = 6%).. Our study demonstrates that 20% of unselected patients with SSc have anti-tPA antibodies and that there is a higher representation of patients with CREST syndrome in this subgroup. The high frequency of pulmonary hypertension in the anti-tPA positive group suggests that these autoantibodies may play a pathogenic role in certain patients with SSc.

Topics: Adult; Aged; Autoantibodies; Female; Fibrin; Humans; Male; Middle Aged; Scleroderma, Systemic; Tissue Plasminogen Activator

It has been previously proposed that there is a primary microvascular abnormality in patients with systemic sclerosis. In this study using conventional light and electron microscopy, immunohistochemistry, and labelled adenosine uptake techniques, changes in the dermal microvasculature have been related to the various clinical stages of skin disease in systemic sclerosis. The earliest pathological changes are seen in clinically normal skin. They constitute changes in endothelial cell function and their consequences. Perivascular oedema is an early feature. With progression in the clinical disease, there is, at first, an inflammatory cell infiltrate into the dermis, particularly the papillary and mid-dermis, and platelet aggregation within vessels. Further clinical progression is associated with increasing dermal fibrosis, loss of adnexae, and vascular effacement. It is postulated that the recruitment of different types of mononuclear cells into the dermis is causally linked with the preceding endothelial cell dysfunction and the subsequent induction of fibroblast proliferation and collagen synthesis.

Topics: Adenosine; Adolescent; Adult; Aged; Autoradiography; Blood Vessels; Endothelium, Vascular; Female; Fibrin; Fibrosis; Humans; Immunohistochemistry; Male; Mast Cells; Microcirculation; Microscopy, Electron; Middle Aged; Scleroderma, Systemic; Skin

Abnormalities in fibrin deposition are implicated in the pathogenesis of vascular occlusion in systemic sclerosis. We have used a technique that involves electrophoresis and densitometric analysis of captured fibrin- and fibrinogen-related antigens to measure the concentration of the individual fibrin and fibrinogen degradation products in 13 patients with systemic sclerosis and in 15 healthy control subjects. As a group, patients with systemic sclerosis had markedly elevated levels of total fibrin-related antigen (p = 0.0007) and D-dimer (p = 0.0004), the terminal degradation product of cross-linked fibrin. The levels of fibrin monomer, an intermediate product in the conversion of fibrinogen to cross-linked fibrin, and of D-monomer, a terminal breakdown fragment of fibrinogen and fibrin monomer, were also elevated (p less than 0.005). We conclude that patients with systemic sclerosis have evidence of enhanced fibrin formation and degradation.

Topics: Adult; Aged; Antigens; Electrophoresis, Polyacrylamide Gel; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Male; Middle Aged; Scleroderma, Localized; Scleroderma, Systemic; Sodium Dodecyl Sulfate

Fibrinolytic activities of whole blood and plasma were determined by 125I-fibrin radiometric assay in 16 normal subjects, and in 11 patients with systemic lupus erythematosus (SLE), 14 with progressive systemic sclerosis (PSS), 23 with venous thromboembolic disease, and 20 patients awaiting elective surgery. Mean whole blood and plasma activities for patients with PSS, and for those awaiting elective surgery, were similar to normal values, as was the mean plasma activity in patients with SLE. However, mean whole blood activity in SLE was significantly decreased compared with normals (p less than 0.05), with mean plasma activity accounting for 44% of mean whole blood activity (compared with 17% in normal subjects), representing a 67% decrease in mean calculated cellular phase activity in SLE, when compared with normals. Since the numbers of cells (neutrophils, monocytes) possibly involved in cellular activity were not decreased, the findings suggest a functional defect in fibrinolytic activity of one or more blood cell types in SLE. An additional finding was the participation of the cellular phase as well as the well-known plasma phase of blood in the fibrinolytic response to thromboembolism.

Topics: Female; Fibrin; Fibrinolysis; Humans; Iodine Radioisotopes; Leukocyte Count; Lupus Erythematosus, Systemic; Male; Monocytes; Neutrophils; Plasma; Plasma Cells; Scleroderma, Systemic; Thrombophlebitis

Topics: Adult; Aged; Antigens; Arteriosclerosis Obliterans; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Immunodiffusion; Male; Middle Aged; Scleroderma, Systemic

Topics: Adult; Arteries; Biopsy; Child; Disseminated Intravascular Coagulation; Female; Fibrin; Graft Rejection; Humans; Hypertension, Malignant; Kidney; Kidney Diseases; Kidney Glomerulus; Kidney Tubular Necrosis, Acute; Pre-Eclampsia; Pregnancy; Scleroderma, Systemic; Transplantation, Homologous; Vascular Diseases

Topics: Adult; Albuminuria; Basement Membrane; Blood Pressure; Capillaries; Complement System Proteins; Creatinine; Female; Fibrin; Fluorescent Antibody Technique; Humans; Immune Sera; Immunoglobulin G; Kidney; Kidney Glomerulus; Lupus Erythematosus, Systemic; Male; Middle Aged; Renal Artery; Scleroderma, Systemic; Urea

Topics: Aged; Basement Membrane; Endothelium; Female; Fibrin; Fluorescent Antibody Technique; Humans; Joint Diseases; Male; Microscopy, Electron; Middle Aged; Necrosis; Rheumatoid Factor; Scleroderma, Systemic; Staining and Labeling; Synovial Fluid; Synovial Membrane; Viscosity

Topics: Arthritis, Rheumatoid; Autopsy; Collagen Diseases; Dermatomyositis; Diagnosis, Differential; Fibrin; Granuloma; Histocytochemistry; Humans; Lung; Lupus Erythematosus, Systemic; Polyarteritis Nodosa; Pulmonary Alveoli; Pulmonary Fibrosis; Rheumatic Fever; Scleroderma, Systemic

Topics: Adrenal Cortex Hormones; Arthritis, Rheumatoid; Cartilage; Collagen Diseases; Connective Tissue; Dermatomyositis; Fibrin; Giant Cell Arteritis; Humans; Lupus Erythematosus, Systemic; Rheumatic Fever; Scleroderma, Systemic