thromboplastin and Aneurysm

Low-density lipoprotein receptor-related protein-1 (LRP1) is a large endocytic and signaling receptor that is widely expressed. In the liver, LRP1 plays an important role in regulating the plasma levels of blood coagulation factor VIII (fVIII) by mediating its uptake and subsequent degradation. fVIII is a key plasma protein that is deficient in hemophilia A and circulates in complex with von Willebrand factor. Because von Willebrand factor blocks binding of fVIII to LRP1, questions remain on the molecular mechanisms by which LRP1 removes fVIII from the circulation. LRP1 also regulates cell surface levels of tissue factor, a component of the extrinsic blood coagulation pathway. This occurs when tissue factor pathway inhibitor bridges the fVII/tissue factor complex to LRP1, resulting in rapid LRP1-mediated internalization and downregulation of coagulant activity. In the vasculature LRP1 also plays protective role from the development of aneurysms. Mice in which the lrp1 gene is selectively deleted in vascular smooth muscle cells develop a phenotype similar to the progression of aneurysm formation in human patient, revealing that these mice are ideal for investigating molecular mechanisms associated with aneurysm formation. Studies suggest that LRP1 protects against elastin fiber fragmentation by reducing excess protease activity in the vessel wall. These proteases include high-temperature requirement factor A1, matrix metalloproteinase 2, matrix metalloproteinase-9, and membrane associated type 1-matrix metalloproteinase. In addition, LRP1 regulates matrix deposition, in part, by modulating levels of connective tissue growth factor. Defining pathways modulated by LRP1 that lead to aneurysm formation and defining its role in thrombosis may allow for more effective intervention in patients.

Topics: Aneurysm; Animals; Atherosclerosis; Blood Coagulation; Elastin; Endocytosis; Extracellular Matrix; Factor VIII; Humans; Lipoproteins, LDL; Liver; Low Density Lipoprotein Receptor-Related Protein-1; Macrophages; Mice; Mice, Knockout; Models, Animal; Models, Molecular; Muscle, Smooth, Vascular; Organ Specificity; Peptide Hydrolases; Platelet-Derived Growth Factor; Protein Conformation; Receptors, LDL; Signal Transduction; Thromboplastin; Transforming Growth Factor beta; Tumor Suppressor Proteins; von Willebrand Factor

We studied the short- and long-term histological responses induced by conventional and modified electronically detachable coils (GDCs) in experimental aneurysms. Eighteen carotid bifurcation aneurysms were produced microsurgically in rabbits. Six animals each were treated either with conventional or with GDCs coated with a mixture of tissue-thromboplastin to enhance intra-aneurysmal thrombus formation and of plasminogen activator inhibitor type-1 (PAI-1) in inhibit intra-aneurysmal clot fibrinolysis. Six served as untreated controls. Follow-up angiograms were obtained immediately and at 3, 6, 9, 12, 17, and 24 weeks after embolization prior to sacrifice of the animals. All aneurysms were studied macroscopically and histopathologically with the coils in situ. Five of six control aneurysms remained patent. Endovascular occlusion rates between > 90% and 100% were achieved in nine of twelve coiled aneurysms. Follow-up angiography demonstrated recanalization and coil compaction in 5 of them. Gross and microscopic histopathological examination revealed a membrane covering the orifice, intra-aneurysmal scar formation, and development of a neo-intima in both treatment groups at 17 and 24 weeks postembolization. The granulation tissue response appeared to be equally distributed in aneurysms treated with either uncoated or coated coils. Further quantitative morphometric studies are needed to prove if a thrombogenic/antithrombolytic coil-coating might be of value in providing a more enduring anatomic result after GDC-treatment of human brain aneurysms.

Topics: Aneurysm; Angiography; Animals; Culture Techniques; Embolization, Therapeutic; Hemostatics; Plasminogen Inactivators; Rabbits; Thromboplastin

Topics: Afibrinogenemia; Aneurysm; Bacteria; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Diagnosis, Differential; Disseminated Intravascular Coagulation; Enzyme Activation; Fibrin; Fibrinogen; Fibrinolysis; Hemostasis; Heparin; Models, Biological; Prothrombin; Sepsis; Shwartzman Phenomenon; Thrombin; Thromboplastin

Topics: Aneurysm; Cerebral Arterial Diseases; Creatinine; Dextrans; Factor VIII; Fibrinolytic Agents; Hemorrhage; Hemorrhagic Disorders; Humans; Kidney Diseases, Cystic; Male; Middle Aged; Platelet Adhesiveness; Prothrombin Time; Thrombin; Thromboplastin