fibrin and Purpura--Thrombotic-Thrombocytopenic

The most striking lesions of thrombotic thrombocytopenic purpura (TTP) are the subendothelial hyaline deposits and multiple occlusive thrombi. They are found in the small arteries, arterioles, and capillaries of many organs, especially the heart, brain, kidneys, and adrenal glands. Immunohistochemical examination demonstrates that the thrombi in TTP are strongly positive for von Willebrand factor (vWF) antigen, but only weakly for fibrinogen/fibrin. Electronmicroscopically, the thrombi in TTP were composed of tightly packed platelets, showing varying degrees of cytoplasmic alteration and degranulation with a small amount of interspersed fibrin and amorphous materials. Many etiological factors causing intravascular platelet aggregation have been postulated, including unusually large vWF multimers, platelet agglutinating proteins and immune abnormalities. All the lesions in TTP are strongly positive for vWF antigen. This result suggests that vWF multimers may play an important role in the pathogenesis of TTP.

Topics: Arteries; Brain; Capillaries; Fibrin; Fibrinogen; Humans; Kidney; Purpura, Thrombotic Thrombocytopenic; von Willebrand Factor

Topics: Blood Coagulation; Burns; Chronic Disease; Disseminated Intravascular Coagulation; Factor V; Factor VIII; Fibrin; Fibrinogen; Fibrinolysis; Hemagglutination Tests; Hemostasis; Humans; Leukemia; Purpura, Thrombotic Thrombocytopenic; Thrombin

Essentials An international collaboration provides a consensus for clinical definitions. This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP). The consensus defines diagnosis, disease monitoring and response to treatment. Requirements for ADAMTS-13 are given.. Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre-eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways. Objectives To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs). Methods The International Working Group has proposed definitions and terminology based on published information and consensus-based recommendations. Conclusion The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune-mediated TTP.

Topics: ADAMTS13 Protein; Adult; Blood Platelets; Child; Complement System Proteins; Consensus; Diagnosis, Differential; Erythrocytes; Female; Fibrin; Hematology; Hemolysis; Hemolytic-Uremic Syndrome; Humans; Inflammation; Platelet Aggregation; Platelet Count; Pregnancy; Purpura, Thrombotic Thrombocytopenic; Recurrence; Remission Induction; Societies, Medical; Terminology as Topic; Thrombotic Microangiopathies; Treatment Outcome; von Willebrand Factor

Essentials Recently, ADAMTS-13 has been shown to undergo substrate induced conformation activation. Conformational quiescence of ADAMTS-13 may serve to prevent off-target proteolysis in plasma. Conformationally active ADAMTS-13 variants are capable of proteolysing the Aα chain of fibrinogen. This should be considered as ADAMTS-13 variants are developed as potential therapeutic agents. Click to hear Dr Zheng's presentation on structure function and cofactor-dependent regulation of ADAMTS-13 SUMMARY: Background Recent work has revealed that ADAMTS-13 circulates in a 'closed' conformation, only fully interacting with von Willebrand factor (VWF) following a conformational change. We hypothesized that this conformational quiescence also maintains the substrate specificity of ADAMTS-13 and that the 'open' conformation of the protease might facilitate proteolytic promiscuity. Objectives To identify a novel substrate for a constitutively active gain of function (GoF) ADAMTS-13 variant (R568K/F592Y/R660K/Y661F/Y665F). Methods Fibrinogen proteolysis was characterized using SDS PAGE and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Fibrin formation was monitored by turbidity measurements and fibrin structure visualized by confocal microscopy. Results ADAMTS-13 exhibits proteolytic activity against the Aα chain of human fibrinogen, but this is only manifest on its conformational activation. Accordingly, the GoF ADAMTS-13 variant and truncated variants such as MDTCS exhibit this activity. The cleavage site has been determined by LC-MS/MS to be Aα chain Lys225-Met226. Proteolysis of fibrinogen by GoF ADAMTS-13 impairs fibrin formation in plasma-based assays, alters clot structure and increases clot permeability. Although GoF ADAMTS-13 does not appear to proteolyse preformed cross-linked fibrin, its proteolytic activity against fibrinogen increases the susceptibility of fibrin to tissue-type plasminogen activator (t-PA)-induced lysis by plasmin and increases the fibrin clearance rate more than 8-fold compared with wild-type (WT) ADAMTS-13 (EC50 values of 3.0 ± 1.7 nm and 25.2 ± 9.7 nm, respectively) in in vitro thrombosis models. Conclusion The 'closed' conformation of ADAMTS-13 restricts its specificity and protects against fibrinogenolysis. Induced substrate promiscuity will be important as ADAMTS-13 variants are developed as potential therapeutic agents against thrombotic thrombocytopenic purpura (TTP) and other cardiovascular diseases.

Topics: ADAMTS13 Protein; Blood Coagulation; Fibrin; Fibrinogen; Fibrinolysin; HEK293 Cells; Humans; Microscopy, Confocal; Protein Conformation; Proteolysis; Purpura, Thrombotic Thrombocytopenic; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Substrate Specificity; Tandem Mass Spectrometry; Thrombosis

Human fibrinogen gamma chain variants, termed gamma' chains, contain a unique 20-residue sequence after gamma chain residue 407 that ends at gamma'427, and is designated gamma'(427L). Full-length (FL) gamma'(427L) chains are constituents of a fibrin-dependent thrombin inhibitory system known as antithrombin I, whereas a gamma' chain processed in vivo, termed gamma'(423P), lacks the C-terminal tetrapeptide EDDL, and does not bind thrombin. Together, the gamma'(423P) and gamma'(427L) chains comprise the total plasma fibrinogen gamma' chain content.. Lowered plasma gamma' chain content (i.e. gamma' chain-containing fibrinogen/total fibrinogen ratio) has been shown to correlate with susceptibility to venous thrombosis, thus prompting this study on the total and FL gamma' chain content in 45 subjects with thrombotic microangiopathy (TMA), a disorder characterized by microvascular thrombosis.. We measured by enzyme-linked immunosorbent assay the total gamma' chain-containing fibrinogen/total fibrinogen (Total gamma'-fgn/Total fgn) ratio and the FL gamma' chain-containing fibrinogen/total fibrinogen (FL gamma'-fgn/Total fgn) ratio in these plasmas and in healthy subjects (n = 87).. In healthy subjects, the mean Total gamma'-fgn/Total fgn ratio was 0.127, whereas the FL gamma'-fgn/Total fgn ratio was somewhat lower at 0.099 (P < 0.0001), a difference reflecting the presence of gamma'(423P) chains. In TMA plasmas, both the Total gamma'-fgn and FL gamma'-fgn/Total fgn ratios (0.099 and 0.084, respectively) were lower than those of their healthy subject counterparts (P < 0.0001).. These findings in TMA suggest that reductions in the gamma' chain content indicate reduced antithrombin I activity that may contribute to microvascular thrombosis in TMA.

Topics: ADAM Proteins; ADAMTS13 Protein; Adult; Aged; Aged, 80 and over; Anemia, Hemolytic; Black or African American; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Female; Fibrin; Fibrinogen; Haplotypes; Humans; Linear Models; Male; Microcirculation; Middle Aged; Polymorphism, Genetic; Purpura, Thrombotic Thrombocytopenic; Reference Values; Syndrome; Thrombosis; White People

Severe deficiency of ADAMTS13 activity was recently found in patients with thrombotic thrombocytopenic purpura (TTP). The great advance associated with these basic and clinical studies on ADAMTS13 is the possible elucidation of the pathogenesis of TMA (thrombotic microangiopathy). However, the exact pathogenetic mechanism in TMA without severe deficiency of ADAMTS13 activity remains unknown due to heterogeneity of the disease. In this study, there were 7 patients with TTP, 7 with HUS, 3 with drug-induced HUS, 1 with VOD, and 1 with IVL out of 19 TMA patients with a moderate deficiency (6-70%) of ADAMTS13 activity. Five of the 7 TTP patients had a poor outcome. Plasma thrombomodulin and t-PA-PAI-1 complex levels in TMA patients with a moderate deficiency of ADAMTS13 activity were significantly higher than those in patients with a severe deficiency of ADAMTS13 activity. These data suggest that the etiology in these patients may be systemic vascular endothelial cell damage.

Topics: ADAM Proteins; ADAMTS13 Protein; Adolescent; Adult; Aged; Biomarkers; Female; Fibrin; Hemolytic-Uremic Syndrome; Humans; Lipoproteins; Male; Metalloendopeptidases; Middle Aged; Peptide Fragments; Protein Precursors; Prothrombin; Purpura, Thrombotic Thrombocytopenic; Thromboplastin

Topics: Adult; Blood Platelets; Fatal Outcome; Female; Fibrin; Humans; Kidney; Multiple Organ Failure; Purpura, Thrombotic Thrombocytopenic; von Willebrand Factor

To determine splenic pathology in thrombotic thrombocytopenic purpura (TTP), 10 spleens and two accessory spleens were studied. The eight women and two men ranged from 20 to 66 years of age (mean age, 39 years). Three spleens were enlarged. Thrombi were noted in arteries and arterioles in nine specimens: no associated inflammation was seen. Periodic acid-Schiff-positive diastase-resistant hyaline subendothelial deposits (SEDs) were present in all cases. Some arterioles showed a transition between thrombi and SEDs. The presence of platelets or platelet-related material in SEDs and thrombi was documented by factor VIII staining. Hyperplasia of B cells and germinal centers was present in 67%, and periarteriolar concentric fibrosis ("onion-skinning") in 58%. Histiocytes showed prominent iron deposits in 92% and hemophagocytosis in 83% of cases. Extramedullary hematopoiesis was present in 42%. Blood lakes, infarcts, and endothelial hyperplasia were rarely noted; microaneurysms were not seen. Ten spleens from patients with idiopathic thrombocytopenic purpura and 10 age-matched control spleens rarely showed SEDs or hemosiderosis and did not show hemophagocytosis or thrombi. We conclude that subendothelial deposits may be related to platelet thrombi incorporated into vessel walls. Germinal centers and periarteriolar concentric fibrosis may indicate an immunologic role in TTP, as in systemic lupus erythematosus.

Topics: Adult; Aged; Arterioles; Blood Platelets; Endothelium; Factor VIII; Female; Fibrin; Hematopoiesis, Extramedullary; Humans; Immunoenzyme Techniques; Male; Middle Aged; Organ Size; Phagocytosis; Platelet Count; Purpura, Thrombotic Thrombocytopenic; Retrospective Studies; Spleen

We collected 23 autopsied cases of thrombotic thrombocytopenic purpura (TTP) and examined them immunohistochemically and electronmicroscopically to elucidate the nature of thrombi and subendothelial deposits. The findings were compared with those of 10 cases of disseminated intravascular coagulation (DIC) and 3 cases of polyarteritis nodosa (PN). Intravascular thrombi and subendothelial hyaline deposits in TTP stained weakly for fibrinogen/fibrin by the PAP technique, while they stained strongly for factor VIII related antigen (FVIIIR: Ag). Electronmicroscopically, thrombi in TTP were composed of numerous, variably degranulated and altered platelets, and a small amount of amorphous materials. Thrombi in DIC were strongly positive for fibrinogen/fibrin, while they were weakly positive for FVIIIR:Ag. Electronmicroscopically they were composed of polymerized fibrin. Fibrinoid necrotic lesions in PN were strongly positive for fibrinogen/fibrin but negative for FVIII R:Ag. Based on these findings, we concluded that thrombi in TTP are essentially platelet thrombi and that subendothelial hyaline deposits may not be a result of increased vascular permeability but may be platelet thrombi incorporated into the arterial wall and covered with newly formed endothelial cells.

Topics: Adolescent; Adult; Aged; Antigens; Disseminated Intravascular Coagulation; Factor VIII; Female; Fibrin; Fibrinogen; Histocytochemistry; Humans; Immunochemistry; Male; Middle Aged; Polyarteritis Nodosa; Purpura, Thrombotic Thrombocytopenic; von Willebrand Factor

Thrombotic thrombocytopenic purpura (TTP) is an uncommon disorder which usually occurs in young adults. It is characterized by a pentad of clinical findings: fever, neurological abnormalities, renal dysfunction, microangiopathic hemolytic anemia and thrombocytopenia. The histological hallmark is the presence of platelet thrombi occluding the microcirculation of multiple organs. The etiology and pathogenesis of disseminated platelet aggregation are uncertain and obviously not uniform in individual patients. Experimental findings suggest that microthrombi may result from intravascular platelet activation or form secondarily at sites of vessel wall damage. The differential diagnosis of TTP includes the hemolytic uremic syndrome in which the microangiopathic changes are exclusively found in the kidneys. When untreated, TTP invariably runs a progressive and fatal course. In recent years, prognosis has been improved by new forms of therapy such as plasmapheresis or infusions of fresh frozen plasma which may lead to recovery in about 80% of patients.

Topics: Blood Coagulation Factors; Blood Coagulation Tests; Diagnosis, Differential; Disseminated Intravascular Coagulation; Fibrin; Humans; Platelet Activating Factor; Platelet Aggregation; Platelet Count; Prognosis; Purpura, Thrombotic Thrombocytopenic; Thrombosis

Topics: Blood Coagulation; Diagnosis, Differential; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Heparin; Humans; Labor, Obstetric; Neoplasms; Pregnancy; Purpura, Thrombotic Thrombocytopenic; Snake Bites; Thrombin

Neuropathologic examination of an autopsy series of 54 patients of various types of CVD revealed a very high frequency of pathologic changes both in brain parenchyma (in 81%) and vessels (in 78%). A broad but continuous spectrum of primary vascular alterations was observed, ranging from fibrinoid deposits in intact or necrotizing vessel walls to fibrohyalinosis and endothelial proliferations. In acute SLE showing LE cells within brain tissues, immune complex deposits were observed for the first time in brain vessels, in addition to similar deposits in the plexus chorioideus and in hematoxylin bodies. Secondary complications are frequently affecting the brain in CVD; they are mainly sequels of systemic atherosclerosis, hypertension, thromboemboli from SLE endocarditis, cardiac, hepatic or renal dysfunctions, or infections and should be clinically differentiated from primary brain involvement in CVD to ensure the appropriate therapeutic measures.

Topics: Arthritis, Rheumatoid; Brain; Cerebral Arteries; Collagen Diseases; Complement C3; Fibrin; Humans; Immunoglobulin G; Lupus Erythematosus, Systemic; Myositis; Polyarteritis Nodosa; Purpura, Thrombotic Thrombocytopenic; Vascular Diseases; Vasculitis

Clot formation occurs preferentially in the choriocapillaris. With intraocular inflammation this clotting begins along the inner surface of the choriocapillaris suggesting that dilatation of the vessels and opening of the endothelial fenestra have initiated the process. With the systemic coagulopathy of thrombotic thrombocytopenia (TTP) and disseminated intravascular coagulopathy (DIC) clotting occurs preferentially in the submacular choriocapillaris, sometimes associated with choroidal hemorrhage and detachment of the retina. These complications are illustrated in the present paper by a patient with TTP showing relatively chronic coagulopathy and by three patients with DIC showing variations of acute coagulopathy.

Topics: Adult; Choroid; Disseminated Intravascular Coagulation; Female; Fibrin; Humans; Male; Middle Aged; Pregnancy; Purpura, Thrombotic Thrombocytopenic; Retinal Detachment

Topics: Adult; Blood Coagulation Tests; Blood Platelets; Child, Preschool; Chromium Radioisotopes; Creatinine; Factor V; Factor VIII; Factor XIII; Female; Fibrin; Fibrinogen; Fibrinolysis; Haptoglobins; Hematocrit; Hemolytic-Uremic Syndrome; Humans; Infant; Male; Middle Aged; Plasminogen; Prothrombin; Purpura, Thrombotic Thrombocytopenic; Thrombin

Topics: Adult; Anti-Bacterial Agents; Bacterial Infections; Blood Vessels; Disseminated Intravascular Coagulation; Drug Hypersensitivity; Female; Fibrin; Humans; Lupus Erythematosus, Systemic; Prednisone; Purpura, Thrombotic Thrombocytopenic; Splenectomy

Topics: Female; Fibrin; Fibrinogen; Humans; Hyalin; Inclusion Bodies; Lupus Erythematosus, Systemic; Purpura, Thrombotic Thrombocytopenic

Topics: Adolescent; Aspirin; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Cell Aggregation; Dipyridamole; Disseminated Intravascular Coagulation; Female; Fibrin; Hematocrit; Heparin; Humans; Hydrocortisone; Purpura, Thrombotic Thrombocytopenic; Remission, Spontaneous; Reticulocytes; Spleen; Splenectomy

Topics: Adult; Animals; Brain; Complement System Proteins; Female; Fibrin; Fluorescent Antibody Technique; Goats; Humans; Immune Sera; Immunodiffusion; Immunoglobulin M; Kidney Glomerulus; Liver; Lung; Myocardium; Purpura, Thrombotic Thrombocytopenic; Spleen

Topics: Aged; Blood Cell Count; Blood Platelets; Fibrin; Hemoglobinometry; Humans; Immunodiffusion; Male; Precipitin Tests; Purpura, Thrombotic Thrombocytopenic

Topics: Adult; Beta-Globulins; Female; Fibrin; Fluorescent Antibody Technique; gamma-Globulins; Histocytochemistry; Humans; Kidney; Kidney Glomerulus; Male; Microscopy, Electron; Microscopy, Fluorescence; Purpura, Thrombotic Thrombocytopenic; Spleen

Topics: Blood Coagulation; Blood Vessels; Fibrin; Fibrinogen; Humans; Hyalin; Pathology; Purpura; Purpura, Thrombotic Thrombocytopenic; Shwartzman Phenomenon; Thrombocytopenia; Thrombosis