The plasma kallikrein-kinin system consists of factor XII, prekallikrein, and high molecular weight kininogen. It was originally recognized as a contact activation system activated by artificial surfaces. However, new evidence indicates there is a proteolytic pathway on cells for prekallikrein activation independent of factor XII. This suggests physiological roles beyond coagulation, such as blood pressure regulation and modulation of thrombosis risk. The system also regulates endothelial cell proliferation, angiogenesis, and apoptosis through cellular signaling. Understanding of this system has evolved from its original characterization as initiating coagulation to recognizing additional vascular biology functions.
Secondary hemostasis - coagulation cascades and lab testsharveenbhusari
This document provides an overview of coagulation factors and mechanisms involved in secondary hemostasis. It describes the intrinsic and extrinsic pathways, key coagulation factors such as fibrinogen, prothrombin, thromboplastin, and von Willebrand factor. It also discusses the fibrinolytic system, natural inhibitors of coagulation, and common laboratory tests used to evaluate coagulation, including specimen collection methods.
Blood Coagulation , ABO blood group & Rh factorSusmitaShaw3
1) The document summarizes blood coagulation, ABO blood group system, and Rh factor. It describes the process of haemostasis including vascular constriction, platelet plug formation, and blood clotting via the intrinsic and extrinsic pathways.
2) It explains the ABO blood group system which is based on the presence or absence of A and B antigens. The four blood groups are A, B, AB, and O depending on which antigens are present. It also describes the corresponding agglutinins (antibodies) found in each blood group.
3) The genetic inheritance of blood groups is discussed where the A, B, and O genes determine the antigens present. The Rh factor, a
This document discusses coagulation factors and blood clotting. It defines coagulation as the process where blood loses fluidity and forms a jelly-like clot. Thirteen coagulation factors are involved in a cascade of reactions to form a clot. The cascade involves the formation of prothrombin activator through the intrinsic and extrinsic pathways, followed by the conversion of prothrombin to thrombin and fibrinogen to fibrin. Deficiencies in specific factors can cause bleeding disorders like hemophilia. The clot then undergoes retraction and may be broken down through fibrinolysis.
Anti coagulationin patient with ckd Prof.Basset El Essawy MD ph DFarragBahbah
1. The document discusses physiology and pathways of coagulation, as well as antiplatelet drugs, anticoagulants, and thrombolytics used to treat coagulation.
2. Standard heparin and low molecular weight heparins are compared, noting differences in molecular weight, bioavailability, monitoring needs, and clearance.
3. New oral anticoagulants are discussed as alternatives to warfarin, noting their benefits of fixed dosing, limited drug interactions and food effects, and lack of routine monitoring needs. However, concerns remain regarding a lack of monitoring methods and proven antidotes.
The document summarizes the blood clotting (coagulation) mechanism. It occurs when blood is shed from damaged blood vessels or tissues. There are two pathways - the extrinsic pathway which is initiated by tissue factor, and the intrinsic pathway initiated by platelets. Both pathways involve a cascade of coagulation factors and ultimately lead to the formation of a prothrombinase complex. This converts prothrombin to thrombin via the common pathway. Thrombin then converts fibrinogen to fibrin to form a mesh and stabilize the platelet plug, sealing the break in the blood vessel.
The cascade theory describes blood coagulation as a series of biochemical reactions that converts soluble fibrinogen into insoluble fibrin clot. It involves the intrinsic and extrinsic pathways that activate coagulation factors in a cascade-like manner, culminating in a common pathway where thrombin converts fibrinogen to fibrin. Feedback mechanisms tightly regulate clot formation to prevent excessive coagulation.
A novel publication form stefano fiorucci lab demonstrates a role for bile acids in regulating arterial vasodilation.
The foinding might have relevance in designing novel ddrug to treat hypertension and metabolic syndrome.
The coagulation system involves a cascade of enzymatic reactions that ultimately result in fibrin clot formation. The cascade can be initiated through either the intrinsic or extrinsic pathway, both of which involve a series of coagulation factor zymogens being activated into active enzyme forms. This leads to thrombin generation and conversion of fibrinogen into fibrin. A number of processes also act to regulate coagulation and prevent excessive clotting, including antithrombin III, protein C, and fibrinolysis.
Secondary hemostasis - coagulation cascades and lab testsharveenbhusari
This document provides an overview of coagulation factors and mechanisms involved in secondary hemostasis. It describes the intrinsic and extrinsic pathways, key coagulation factors such as fibrinogen, prothrombin, thromboplastin, and von Willebrand factor. It also discusses the fibrinolytic system, natural inhibitors of coagulation, and common laboratory tests used to evaluate coagulation, including specimen collection methods.
Blood Coagulation , ABO blood group & Rh factorSusmitaShaw3
1) The document summarizes blood coagulation, ABO blood group system, and Rh factor. It describes the process of haemostasis including vascular constriction, platelet plug formation, and blood clotting via the intrinsic and extrinsic pathways.
2) It explains the ABO blood group system which is based on the presence or absence of A and B antigens. The four blood groups are A, B, AB, and O depending on which antigens are present. It also describes the corresponding agglutinins (antibodies) found in each blood group.
3) The genetic inheritance of blood groups is discussed where the A, B, and O genes determine the antigens present. The Rh factor, a
This document discusses coagulation factors and blood clotting. It defines coagulation as the process where blood loses fluidity and forms a jelly-like clot. Thirteen coagulation factors are involved in a cascade of reactions to form a clot. The cascade involves the formation of prothrombin activator through the intrinsic and extrinsic pathways, followed by the conversion of prothrombin to thrombin and fibrinogen to fibrin. Deficiencies in specific factors can cause bleeding disorders like hemophilia. The clot then undergoes retraction and may be broken down through fibrinolysis.
Anti coagulationin patient with ckd Prof.Basset El Essawy MD ph DFarragBahbah
1. The document discusses physiology and pathways of coagulation, as well as antiplatelet drugs, anticoagulants, and thrombolytics used to treat coagulation.
2. Standard heparin and low molecular weight heparins are compared, noting differences in molecular weight, bioavailability, monitoring needs, and clearance.
3. New oral anticoagulants are discussed as alternatives to warfarin, noting their benefits of fixed dosing, limited drug interactions and food effects, and lack of routine monitoring needs. However, concerns remain regarding a lack of monitoring methods and proven antidotes.
The document summarizes the blood clotting (coagulation) mechanism. It occurs when blood is shed from damaged blood vessels or tissues. There are two pathways - the extrinsic pathway which is initiated by tissue factor, and the intrinsic pathway initiated by platelets. Both pathways involve a cascade of coagulation factors and ultimately lead to the formation of a prothrombinase complex. This converts prothrombin to thrombin via the common pathway. Thrombin then converts fibrinogen to fibrin to form a mesh and stabilize the platelet plug, sealing the break in the blood vessel.
The cascade theory describes blood coagulation as a series of biochemical reactions that converts soluble fibrinogen into insoluble fibrin clot. It involves the intrinsic and extrinsic pathways that activate coagulation factors in a cascade-like manner, culminating in a common pathway where thrombin converts fibrinogen to fibrin. Feedback mechanisms tightly regulate clot formation to prevent excessive coagulation.
A novel publication form stefano fiorucci lab demonstrates a role for bile acids in regulating arterial vasodilation.
The foinding might have relevance in designing novel ddrug to treat hypertension and metabolic syndrome.
The coagulation system involves a cascade of enzymatic reactions that ultimately result in fibrin clot formation. The cascade can be initiated through either the intrinsic or extrinsic pathway, both of which involve a series of coagulation factor zymogens being activated into active enzyme forms. This leads to thrombin generation and conversion of fibrinogen into fibrin. A number of processes also act to regulate coagulation and prevent excessive clotting, including antithrombin III, protein C, and fibrinolysis.
Sima lev: Lipid Transfer Proteins and Membrane Contact Sites in Human CancerSima Lev
Lipid-transfer proteins (LTPs) were initially discovered as cytosolic factors that facilitate lipid transport between membrane bilayers in vitro. Since then, many LTPs have been isolated from bacteria, plants, yeast, and mammals, and extensively studied in cell-free systems and intact cells. A major advance in the LTP field was associated with the discovery of intracellular membrane contact sites (MCSs), small cytosolic gaps between the endoplasmic reticulum (ER) and other cellular membranes, which accelerate lipid transfer by LTPs. As LTPs modulate the distribution of lipids within cellular membranes, and many lipid species function as second messengers in key signaling pathways that control cell survival, proliferation, and migration, LTPs have been implicated in cancer-associated signal transduction cascades. Increasing evidence suggests that LTPs play an important role in cancer progression and metastasis. This review by Sima Lev describes how different LTPs as well as MCSs can contribute to cell transformation and malignant phenotype, and discusses how “aberrant” MCSs are associated with tumorigenesis in human.
Hemostasis is the process by which bleeding is stopped. It involves three main systems - the coagulation, fibrinolytic, and anticoagulation systems - working in balance. The coagulation system forms a fibrin clot to seal a break in a blood vessel, while the fibrinolytic system later dissolves the clot, and the anticoagulation system regulates clotting to prevent excessive clot formation. Key components include platelets, coagulation factors, fibrinogen, and inhibitors such as antithrombin. An intact endothelium also plays an important role in hemostasis.
Secondary Haemostasis involves the formation of fibrin clots via the blood coagulation cascade. This involves complex sequential reactions between coagulation factors. The coagulation factors are classified based on their physical properties like molecular weight or functional properties like being substrates, cofactors, or enzymes. Vitamin K plays an important role by allowing coagulation factors to bind to phospholipid surfaces. The coagulation cascade is tightly regulated by naturally occurring inhibitors like antithrombin III and protein C to prevent excessive clotting.
This document provides an overview of the cell-based model of hemostasis and various coagulation assays. It discusses the cell-based model which more accurately explains coagulation in vivo compared to the traditional cascade model. It occurs in three phases: initiation, amplification, and propagation. Platelets and thrombin are central. Various coagulation assays are then described, including prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, thrombin time, D-dimer, and fibrin degradation products. The clinical utility of D-dimer for diagnosing venous thromboembolism is discussed. Two case studies are then presented to demonstrate how the coagulation tests and their results
Fibrinolysis is the process of dissolving blood clots through the activation of plasminogen into plasmin. Plasmin is the main enzyme that degrades fibrin clots. Plasminogen is activated by plasminogen activators such as tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). These activators help initiate a cascade of reactions that results in the breakdown of fibrin clots. There are also inhibitors that help regulate fibrinolysis, with alpha-2-antiplasmin being the most important naturally occurring inhibitor of plasmin to prevent excessive clot breakdown.
The document lists 11 coagulation factors involved in the blood clotting process, along with their names, sources, and in some cases additional details. Factor III is produced by damaged tissues and activated platelets. Factors I, II, V, VII, VIII, IX, X, XI, and XIII are produced by the liver, while factors IV, V, and XIII also have additional sources.
L15 b bleeding disorders my lecture (2)Bruno Mmassy
This document discusses laboratory tests for haemostatic functions and the processes involved in hemostasis. It describes how platelets form the primary hemostatic plug at the site of injury within 20 seconds. The coagulation cascade then activates through the extrinsic and intrinsic pathways to form a fibrin clot through the coagulation factors, strengthening the platelet plug. Screening tests for hemostasis include bleeding time, prothrombin time, and activated partial thromboplastin time. Specific factor assays and platelet function tests are also used.
1) Vascular smooth muscle cells can switch between a contractile phenotype and a synthetic phenotype in response to extracellular signals, and deregulation of this process underlies several vascular disorders.
2) The study found that microRNA miR-21 and miR-221 play important roles in regulating the phenotypic switching of vascular smooth muscle cells. miR-21 promotes the contractile phenotype while miR-221 promotes the synthetic phenotype.
3) The study showed that BMP signaling increases miR-21 levels post-transcriptionally through an interaction of Smad proteins with the microRNA processing complex, and this promotes smooth muscle cell differentiation. PDGF increases miR-221 levels transcriptionally to promote de-differentiation.
This document provides an overview of the coagulation system. It begins with an introduction to the coagulation cascade and hemostasis. It then discusses the intrinsic and extrinsic pathways in more detail, focusing on the complexes formed and the factors involved such as tissue factor and thrombin. The document also covers anticoagulation processes mediated by the endothelium like heparan sulfate and protein C. It concludes with explanations of fibrinolysis and the role of vitamin K in carboxylating coagulation factors.
This document summarizes the key components of the hemostatic (blood clotting) system. It describes how platelets adhere to sites of injury via receptors like GpIb-IX-V and GpIa-IIa, become activated by collagen and thrombin binding receptors like GpVI and PARs, and aggregate together via GpIIb-IIIa receptors crosslinking with fibrinogen. This platelet plug formation is balanced by anti-coagulant factors. Inherited disorders of platelet adhesion, activation or secretion proteins can cause bleeding disorders. The coagulation cascade is initiated at sites of injury by tissue factor binding Factor VIIa and activating downstream coagulation factors X and IX. Ultimately thrombin is
This study examined the effects of fluoranthene (FLA) exposure on Xenopus laevis embryos. The key findings were:
1) Exposure to FLA was associated with abnormal cardiac pacemaker and conduction activity, including tachycardia and atrioventricular block.
2) FLA exposure increased expression of the cytochrome P450 gene CYP1A, suggesting it acts as an aryl hydrocarbon receptor agonist.
3) Low doses of FLA increased expression of the cardiac transcription factors tbx5 and nkx2.5, which are essential for heart development, suggesting a potential low-dose effect.
Blood coagulation, also known as hemostasis, is the process by which blood changes from a liquid to a solid gel-like substance. It involves three stages: vasoconstriction, formation of a platelet plug, and coagulation of blood. When a blood vessel is injured, a series of reactions are initiated through the intrinsic and extrinsic pathways, ultimately resulting in a cross-linked fibrin mesh that traps blood cells to form a clot. Coagulation is tightly regulated by several mechanisms to prevent excessive clotting. Deficiencies or defects in the coagulation cascade can result in bleeding disorders.
Hemostasis is the process by which bleeding is stopped. It occurs via mechanical, chemical, and thermal means. Mechanical hemostasis involves direct pressure, gauze packing, and suturing or ligating cut blood vessels. Chemical hemostasis occurs via platelet plug formation and blood coagulation, while thermal hemostasis involves vasoconstriction to reduce blood flow to the site of injury. Together, these processes form a clot to seal the damaged vessel until tissue repair can take place.
This study identifies molecular chaperones that regulate the endoplasmic reticulum (ER) quality control of the thiazide-sensitive NaCl cotransporter (NCC). NCC forms complexes with the core chaperones Hsp90, Hsp70, and Hsp40 in the cytoplasm. Disruption of Hsp90 function accelerates NCC degradation, indicating Hsp90 promotes NCC folding. The cochaperones CHIP and HOP differentially regulate NCC turnover, with CHIP promoting degradation and HOP favoring biogenesis. Adjusting the folding environment enhances wild type NCC maturation but not disease mutants, which interact more strongly with Hsp70/Hsp40 and are selected for ER
what is blood clotting
what are clotting factors
list of pathways
names of blood clotting factors
calcium and its role in coagulation of blood
calcium as a co-factor during blood clot
aggregation of platelets by calcium]
activation of factors by calcium
role of calcium in activation of co factors
examples
The document is a thesis written by Ketul Desai on the role of ARNT in cardiac tissue during chronic hypoxia. It includes an abstract that hypothesizes ARNT levels will not change in response to chronic hypoxia exposure in cardiac tissue. The methods section describes exposing mice to chronic hypoxia for 3 weeks and analyzing ARNT levels in cardiac and skeletal muscle tissue via western blot. The results section found no significant difference in ARNT levels between normoxic and hypoxic tissues but a significant difference in mouse weights. The conclusion is that the findings are consistent with the initial hypothesis that ARNT levels would remain unchanged with chronic hypoxia exposure.
The Blood and Hemostasis and Blood CoagulationAmany Elsayed
The document discusses the functions of blood and its components. Blood transports oxygen, nutrients, hormones, and removes waste throughout the body via circulation. It is composed of plasma and formed elements like red blood cells, white blood cells, and platelets. Red blood cells contain hemoglobin which binds oxygen in the lungs and releases it in tissues, enabling gas exchange. Blood also maintains homeostasis by regulating pH and temperature. Problems with blood composition or circulation can impair tissue function.
This document provides information on anticoagulant therapy and laboratory monitoring. It discusses the goals and indications for anticoagulant therapy including preventing thrombosis. It describes the traditional approach using heparin, coumarins, and antiplatelet drugs. Assays for monitoring anticoagulant therapy include global screening assays like PT, aPTT, and TT as well as more specific chromogenic assays. The mechanisms and monitoring of oral anticoagulants like warfarin are explained in detail. Warfarin inhibits vitamin K and factors II, VII, IX and X. Polymorphisms affecting warfarin metabolism and response are also covered. The mechanisms and uses of unfractionated and low molecular weight hepar
This document discusses the processes of hemostasis, thrombosis, and fibrinolysis. It defines key terms like blood clot, platelet, fibrin, coagulation cascade, and anticoagulants. The document describes the steps of primary hemostasis which involves platelet adhesion and activation at the site of injury. It also outlines the secondary hemostasis process known as the coagulation cascade that generates thrombin and ultimately forms a fibrin clot to stop bleeding. The roles of fibrinolysis and anticoagulant pathways in regulating clot formation are also summarized.
This document discusses Trypanosoma, a genus of parasitic protozoa. It notes that Trypanosoma have a corkscrew-like motion and require more than one host to complete their lifecycle. The document outlines that Trypanosoma bruci causes sleeping sickness, while Trypanosoma cruzi causes Chagas disease. It also summarizes the lifecycles of Trypanosoma bruci and Trypanosoma cruzi, including their transmission between hosts by vectors like tsetse flies and their pathogenesis in humans.
African trypanosomiasis, also known as sleeping sickness, is caused by microscopic parasites of the species Trypanosoma brucei which is transmitted by the tsetse fly found in rural Africa. The disease has been a serious public health problem in some regions of sub-Saharan Africa. Symptoms in advanced stages include alteration of biological clocks, confusion, slurred speech, seizures and difficulty walking or talking which can lead to death if not treated. Treatment options include drugs like diminazene and suramin, while prevention focuses on reducing reservoirs of infection and the presence of tsetse flies through screening programs and early diagnosis.
Sima lev: Lipid Transfer Proteins and Membrane Contact Sites in Human CancerSima Lev
Lipid-transfer proteins (LTPs) were initially discovered as cytosolic factors that facilitate lipid transport between membrane bilayers in vitro. Since then, many LTPs have been isolated from bacteria, plants, yeast, and mammals, and extensively studied in cell-free systems and intact cells. A major advance in the LTP field was associated with the discovery of intracellular membrane contact sites (MCSs), small cytosolic gaps between the endoplasmic reticulum (ER) and other cellular membranes, which accelerate lipid transfer by LTPs. As LTPs modulate the distribution of lipids within cellular membranes, and many lipid species function as second messengers in key signaling pathways that control cell survival, proliferation, and migration, LTPs have been implicated in cancer-associated signal transduction cascades. Increasing evidence suggests that LTPs play an important role in cancer progression and metastasis. This review by Sima Lev describes how different LTPs as well as MCSs can contribute to cell transformation and malignant phenotype, and discusses how “aberrant” MCSs are associated with tumorigenesis in human.
Hemostasis is the process by which bleeding is stopped. It involves three main systems - the coagulation, fibrinolytic, and anticoagulation systems - working in balance. The coagulation system forms a fibrin clot to seal a break in a blood vessel, while the fibrinolytic system later dissolves the clot, and the anticoagulation system regulates clotting to prevent excessive clot formation. Key components include platelets, coagulation factors, fibrinogen, and inhibitors such as antithrombin. An intact endothelium also plays an important role in hemostasis.
Secondary Haemostasis involves the formation of fibrin clots via the blood coagulation cascade. This involves complex sequential reactions between coagulation factors. The coagulation factors are classified based on their physical properties like molecular weight or functional properties like being substrates, cofactors, or enzymes. Vitamin K plays an important role by allowing coagulation factors to bind to phospholipid surfaces. The coagulation cascade is tightly regulated by naturally occurring inhibitors like antithrombin III and protein C to prevent excessive clotting.
This document provides an overview of the cell-based model of hemostasis and various coagulation assays. It discusses the cell-based model which more accurately explains coagulation in vivo compared to the traditional cascade model. It occurs in three phases: initiation, amplification, and propagation. Platelets and thrombin are central. Various coagulation assays are then described, including prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, thrombin time, D-dimer, and fibrin degradation products. The clinical utility of D-dimer for diagnosing venous thromboembolism is discussed. Two case studies are then presented to demonstrate how the coagulation tests and their results
Fibrinolysis is the process of dissolving blood clots through the activation of plasminogen into plasmin. Plasmin is the main enzyme that degrades fibrin clots. Plasminogen is activated by plasminogen activators such as tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). These activators help initiate a cascade of reactions that results in the breakdown of fibrin clots. There are also inhibitors that help regulate fibrinolysis, with alpha-2-antiplasmin being the most important naturally occurring inhibitor of plasmin to prevent excessive clot breakdown.
The document lists 11 coagulation factors involved in the blood clotting process, along with their names, sources, and in some cases additional details. Factor III is produced by damaged tissues and activated platelets. Factors I, II, V, VII, VIII, IX, X, XI, and XIII are produced by the liver, while factors IV, V, and XIII also have additional sources.
L15 b bleeding disorders my lecture (2)Bruno Mmassy
This document discusses laboratory tests for haemostatic functions and the processes involved in hemostasis. It describes how platelets form the primary hemostatic plug at the site of injury within 20 seconds. The coagulation cascade then activates through the extrinsic and intrinsic pathways to form a fibrin clot through the coagulation factors, strengthening the platelet plug. Screening tests for hemostasis include bleeding time, prothrombin time, and activated partial thromboplastin time. Specific factor assays and platelet function tests are also used.
1) Vascular smooth muscle cells can switch between a contractile phenotype and a synthetic phenotype in response to extracellular signals, and deregulation of this process underlies several vascular disorders.
2) The study found that microRNA miR-21 and miR-221 play important roles in regulating the phenotypic switching of vascular smooth muscle cells. miR-21 promotes the contractile phenotype while miR-221 promotes the synthetic phenotype.
3) The study showed that BMP signaling increases miR-21 levels post-transcriptionally through an interaction of Smad proteins with the microRNA processing complex, and this promotes smooth muscle cell differentiation. PDGF increases miR-221 levels transcriptionally to promote de-differentiation.
This document provides an overview of the coagulation system. It begins with an introduction to the coagulation cascade and hemostasis. It then discusses the intrinsic and extrinsic pathways in more detail, focusing on the complexes formed and the factors involved such as tissue factor and thrombin. The document also covers anticoagulation processes mediated by the endothelium like heparan sulfate and protein C. It concludes with explanations of fibrinolysis and the role of vitamin K in carboxylating coagulation factors.
This document summarizes the key components of the hemostatic (blood clotting) system. It describes how platelets adhere to sites of injury via receptors like GpIb-IX-V and GpIa-IIa, become activated by collagen and thrombin binding receptors like GpVI and PARs, and aggregate together via GpIIb-IIIa receptors crosslinking with fibrinogen. This platelet plug formation is balanced by anti-coagulant factors. Inherited disorders of platelet adhesion, activation or secretion proteins can cause bleeding disorders. The coagulation cascade is initiated at sites of injury by tissue factor binding Factor VIIa and activating downstream coagulation factors X and IX. Ultimately thrombin is
This study examined the effects of fluoranthene (FLA) exposure on Xenopus laevis embryos. The key findings were:
1) Exposure to FLA was associated with abnormal cardiac pacemaker and conduction activity, including tachycardia and atrioventricular block.
2) FLA exposure increased expression of the cytochrome P450 gene CYP1A, suggesting it acts as an aryl hydrocarbon receptor agonist.
3) Low doses of FLA increased expression of the cardiac transcription factors tbx5 and nkx2.5, which are essential for heart development, suggesting a potential low-dose effect.
Blood coagulation, also known as hemostasis, is the process by which blood changes from a liquid to a solid gel-like substance. It involves three stages: vasoconstriction, formation of a platelet plug, and coagulation of blood. When a blood vessel is injured, a series of reactions are initiated through the intrinsic and extrinsic pathways, ultimately resulting in a cross-linked fibrin mesh that traps blood cells to form a clot. Coagulation is tightly regulated by several mechanisms to prevent excessive clotting. Deficiencies or defects in the coagulation cascade can result in bleeding disorders.
Hemostasis is the process by which bleeding is stopped. It occurs via mechanical, chemical, and thermal means. Mechanical hemostasis involves direct pressure, gauze packing, and suturing or ligating cut blood vessels. Chemical hemostasis occurs via platelet plug formation and blood coagulation, while thermal hemostasis involves vasoconstriction to reduce blood flow to the site of injury. Together, these processes form a clot to seal the damaged vessel until tissue repair can take place.
This study identifies molecular chaperones that regulate the endoplasmic reticulum (ER) quality control of the thiazide-sensitive NaCl cotransporter (NCC). NCC forms complexes with the core chaperones Hsp90, Hsp70, and Hsp40 in the cytoplasm. Disruption of Hsp90 function accelerates NCC degradation, indicating Hsp90 promotes NCC folding. The cochaperones CHIP and HOP differentially regulate NCC turnover, with CHIP promoting degradation and HOP favoring biogenesis. Adjusting the folding environment enhances wild type NCC maturation but not disease mutants, which interact more strongly with Hsp70/Hsp40 and are selected for ER
what is blood clotting
what are clotting factors
list of pathways
names of blood clotting factors
calcium and its role in coagulation of blood
calcium as a co-factor during blood clot
aggregation of platelets by calcium]
activation of factors by calcium
role of calcium in activation of co factors
examples
The document is a thesis written by Ketul Desai on the role of ARNT in cardiac tissue during chronic hypoxia. It includes an abstract that hypothesizes ARNT levels will not change in response to chronic hypoxia exposure in cardiac tissue. The methods section describes exposing mice to chronic hypoxia for 3 weeks and analyzing ARNT levels in cardiac and skeletal muscle tissue via western blot. The results section found no significant difference in ARNT levels between normoxic and hypoxic tissues but a significant difference in mouse weights. The conclusion is that the findings are consistent with the initial hypothesis that ARNT levels would remain unchanged with chronic hypoxia exposure.
The Blood and Hemostasis and Blood CoagulationAmany Elsayed
The document discusses the functions of blood and its components. Blood transports oxygen, nutrients, hormones, and removes waste throughout the body via circulation. It is composed of plasma and formed elements like red blood cells, white blood cells, and platelets. Red blood cells contain hemoglobin which binds oxygen in the lungs and releases it in tissues, enabling gas exchange. Blood also maintains homeostasis by regulating pH and temperature. Problems with blood composition or circulation can impair tissue function.
This document provides information on anticoagulant therapy and laboratory monitoring. It discusses the goals and indications for anticoagulant therapy including preventing thrombosis. It describes the traditional approach using heparin, coumarins, and antiplatelet drugs. Assays for monitoring anticoagulant therapy include global screening assays like PT, aPTT, and TT as well as more specific chromogenic assays. The mechanisms and monitoring of oral anticoagulants like warfarin are explained in detail. Warfarin inhibits vitamin K and factors II, VII, IX and X. Polymorphisms affecting warfarin metabolism and response are also covered. The mechanisms and uses of unfractionated and low molecular weight hepar
This document discusses the processes of hemostasis, thrombosis, and fibrinolysis. It defines key terms like blood clot, platelet, fibrin, coagulation cascade, and anticoagulants. The document describes the steps of primary hemostasis which involves platelet adhesion and activation at the site of injury. It also outlines the secondary hemostasis process known as the coagulation cascade that generates thrombin and ultimately forms a fibrin clot to stop bleeding. The roles of fibrinolysis and anticoagulant pathways in regulating clot formation are also summarized.
This document discusses Trypanosoma, a genus of parasitic protozoa. It notes that Trypanosoma have a corkscrew-like motion and require more than one host to complete their lifecycle. The document outlines that Trypanosoma bruci causes sleeping sickness, while Trypanosoma cruzi causes Chagas disease. It also summarizes the lifecycles of Trypanosoma bruci and Trypanosoma cruzi, including their transmission between hosts by vectors like tsetse flies and their pathogenesis in humans.
African trypanosomiasis, also known as sleeping sickness, is caused by microscopic parasites of the species Trypanosoma brucei which is transmitted by the tsetse fly found in rural Africa. The disease has been a serious public health problem in some regions of sub-Saharan Africa. Symptoms in advanced stages include alteration of biological clocks, confusion, slurred speech, seizures and difficulty walking or talking which can lead to death if not treated. Treatment options include drugs like diminazene and suramin, while prevention focuses on reducing reservoirs of infection and the presence of tsetse flies through screening programs and early diagnosis.
Trypanosoma cruzi causa la tripanosomiasis americana o enfermedad de Chagas. Se transmite a humanos a través de la picadura del insecto triatomíneo. En humanos, el parásito pasa por distintas formas morfológicas y etapas de su ciclo de vida que incluyen amastigotes, tripomastigotes y epimastigotes. La enfermedad crónica puede causar daños cardíacos e intestinales irreversibles. El diagnóstico incluye observación microscópica del parásito
This is the presentation on Trypanosomiasis that covers classification and diseases caused by Trypanosoma, its life cycle, Geographical distribution, Transmission, diagnosis and treatment and finally its scenario in India.
Some flow charts have been taken from published articles, that can be searched directly from net.
The document provides an overview and learning module on coagulation and hemostasis created by a medical student at the University of Vermont College of Medicine. It begins with definitions of key terms and an overview of primary and secondary hemostasis. It then reviews the components of the coagulation cascade including the extrinsic, intrinsic, and common pathways. It discusses pharmacologic considerations and the roles of the endothelium and subendothelium. Finally, it provides a detailed review of coagulation and hemostasis in a series of slides for students to test their knowledge.
The document discusses the process of coagulation and fibrinolysis. It describes the three major systems involved - the vessel wall, platelets, and the coagulation cascade. The coagulation cascade involves multiple coagulation factors and pathways. Fibrinolysis is the breakdown of clots by plasmin. The document also discusses inhibitors and regulators of coagulation, including the roles of vitamin K, thrombomodulin, and tissue factor pathway inhibitor.
This document discusses coagulants and anticoagulants used in medicinal chemistry. It provides background on blood coagulation pathways and factors. Coagulants discussed include vitamin K, fibrinogen, antihaemophilic factor, desmopressin, and others. Vitamin K is important for the synthesis of clotting factors and its deficiency can cause bleeding. Anticoagulants lower blood coagulability and include heparins, low molecular weight heparins, danaparoid, lepirudin, ancrod, and oral coumarin derivatives like warfarin.
If the many beneficial effects of the chemokines can be preserved, such efforts hold great promise for uncovering new therapies for inflammatory and immunologic disease
This document discusses biological cascades and blood clotting mechanisms. It specifically focuses on the roles of Vitamin K and two types of anticoagulants - coumarins like warfarin and heparin derivatives. Vitamin K is necessary for blood clotting as it activates coagulation factors through carboxylation. Warfarin works by inhibiting the enzyme that recycles Vitamin K, preventing coagulation factor activation. Heparin binds to proteins to inhibit thrombin and Factor Xa formation, disrupting the clotting cascade. Both drugs have similar anticoagulant effects but work through different mechanisms.
Chemokines are small proteins that direct the movement of white blood cells to sites of injury or infection. They are classified based on structural characteristics like the positioning of conserved cysteine residues. The four main classes are CC, CXC, C, and CX3C chemokines. Chemokines bind to G protein-coupled receptors on cells and signal through G proteins and secondary messengers to induce cell migration. Chemokines play roles in processes like inflammation, immunity, and cancer and are implicated in diseases like HIV, arthritis, and transplant rejection.
This document discusses radiopharmaceuticals used for infection imaging. It begins by describing gallium-67 citrate, which was the first infection-seeking radiopharmaceutical and is still used today, though more limited. Radiolabeled leukocytes are now usually preferred. FDG is also increasingly used. The document then discusses the pathophysiology of inflammation and infection in more detail. It describes how various radiopharmaceuticals, including gallium-67 citrate and radiolabeled leukocytes, are taken up at sites of infection and their mechanisms of uptake, distributions, and dosimetry.
This document provides a review of the pathophysiology and management of severe hyperkalemia. It discusses two systems that regulate potassium levels: one that controls short-term internal balance through cell membrane equilibrium, and one that controls long-term external balance through renal elimination. For severe hyperkalemia, the initial treatment focuses on membrane stabilization with calcium, potassium redistribution with insulin or beta-agonists, and enhanced elimination with loop diuretics or sodium polystyrene sulfonate. Rational use of these tools can successfully treat life-threatening hyperkalemia.
Mistry Shivangi,M.Pharm Pharmacology, Assistant Professor, Bhagwan Mahavir College of Pharmacy, clinical sign of inflammation, type, chemical mediator of inflammation, wound healing
This lecture was the opening lecture on the ‘Physiology of Coagulation’ at the Continuing Medical Education (CME) Grand Rounds, 2011. Organised by Kuwait Anesthesia Council, Kuwait
This document discusses the evaluation of recombinant clotting factor VIII concentrates. It analyzes the heterogeneity and purity of different recombinant factor VIII preparations before and after thrombin digestion using techniques like SDS-PAGE, 2DE electrophoresis, and gel digestion. The results show bands corresponding to truncated recombinant factor VIII as well as the presence of contaminating proteins like haptoglobin and albumin. Thrombin cleavage was found to remove bands in the SDS-PAGE of the inactive factor VIII pro-cofactor. The conclusions state that 2DE is better than SDS-PAGE for assessing purity and that the use of recombinant factor VIII does not rule out contaminants.
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The plasma kallikrein kinin system its evolution from contact activation
1. Journal of Thrombosis and Haemostasis, 5: 2323–2329
REVIEW ARTICLE
The plasma kallikrein–kinin system: its evolution from contact
activation
A . H . S C H M A I E R and K . R . M C C R A E
Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University and University Hospitals Case Medical Center,
Cleveland, OH, USA
To cite this article: Schmaier AH, McCrae KR. The plasma kallikrein–kinin system: its evolution from contact activation. J Thromb Haemost 2007; 5:
2323–9.
review will outline physiologic activities of the plasma KKS
Summary. The plasma kallikrein–kinin system consists of the that are not emphasized in other recent reviews [1,2].
proteins factor XII (FXII), prekallikrein (PK), and high FXII deficiency (Hageman trait) was discovered by Ratnoff
molecular weight kininogen. It was first recognized as a sur- and Colopy in an individual who had prolonged blood clotting
face-activated coagulation system that is activated when blood times without bleeding [3]. Activation of FXII results in FXI
or plasma interacts with artificial surfaces. Although surface- activation, giving rise to the coagulation cascade [4]. As result
activated contact activation occurs in vivo in the case of tissue of elucidating non-FXII-deficient etiologies for isolated pro-
destruction or a developing thrombus, the physiologic basis for longed activated partial thromboplastin times (APTT), plasma
the activation and function of this system has not been PK and HK were discovered [5,6]. These proteins influence the
delineated. New investigations indicate that there is a proteo- 200 million surface-activated coagulation tests, APTTs and
lytic pathway on cells for PK activation independent of FXII. activated clotting times performed annually in the USA. New
This pathway for PK with subsequent FXII activation indicates interest in FXII has arisen since it has been observed that FXII-
physiologic activities. These activities include blood pressure deficient mice have reduced thrombus compared to the wild
regulation and modulation of thrombosis risk independently of type [7]. Furthermore, bradykinin (BK) B2 receptor (B2R)-
hemostasis. Furthermore, they include regulation of endothelial deficient mice also have reduced thrombosis risk [8]. C1 esterase
cell proliferation, angiogenesis and apoptosis through a cellular- inhibitor (C1INH), the SERPIN inhibitor of the enzymes of
based, outside-in signaling system. The present characteriza- this system, accounts for 90% of inhibition of FXIIa and 50%
tions of this system, which incorrectly had been thought to of inhibition of plasma kallikrein [9,10] (Table 2). Although
initiate coagulation, represent an evolution of understanding in plasminogen activator inhibitor-1 and protein C inhibitor,
this field. mole for mole, may be more potent inhibitors of plasma
kallikrein than C1INH, the intravascular concentration of
Introduction C1INH is highest, making it the most important (Table 2).
C1INH deficiency is the etiology of hereditary angioedema, a
Appreciation of the plasma kallikrein–kinin system (KKS) has
disorder associated with unregulated BK formation, producing
grown. The KKS consists of two zymogens, factor XII (FXII)
secondary angioedema in humans and mice [11].
and prekallikrein (PK), and one substrate/cofactor, high
molecular weight kininogen (HK) (Table 1). These proteins
influence surface-activated in vitro coagulation assays, but Contact activation of FXII and the proteins of the plasma
deficiencies are not associated with bleeding. Recent studies KKS
indicate activities in vascular biology, including modulation of
The three proteins (FXII, PK, and HK) of the plasma KKS are
thrombosis risk independently of blood coagulation. This
called Ôcontact factorsÕ because, until recently (see next section),
there was no known mechanism for their initiation of activation
other than FXII autoactivation on surfaces [2,3]. Autoactiva-
Correspondence: Alvin H. Schmaier, Case Western Reserve
tion is the event where zymogen FXII becomes an enzyme in the
University, University Hospital Case Medical Center, Division of
presence of a negatively charged surface, a process twentynine-
Hematology and Oncology, 10900 Euclid Avenue WRB2-130,
Cleveland, OH 44106-7284, USA.
fold less efficient than activation by plasma kallikrein [12]
Tel.: +1 216 368 1172; fax: +1 216 368 3014; e-mail: (Table 1). The biochemistry of this phenomenon is not under-
schmaier@case.edu stood, but recent studies using sum frequency generation
vibrational spectroscopy indicate that FXII autoactivation at
Received 3 August 2007, accepted 14 September 2007 the molecular level occurs by imposing specific orientation and
Ó 2007 International Society on Thrombosis and Haemostasis
2. 2324 A. H. Schmaier and K. R. McCrae
Table 1 Enzymes/substrates of the plasma kallikrein–kinin system
Enzyme Substrate Kinetics Reference
a-Factor (F) XIIa Prekallikrein 1.8 lM Km; kcat/Km = 0.57 lM [87]
FXI – [88]
Complement C1 – [89]
FVII – [90]
Plasminogen – [91]
High-Mr kininogen – [89]
b-FXIIa Prekallikrein 2.1 lM Km; kcat/Km = 1.67 lM [87]
Autoactivation of FXII FXII 2.4 lM Km; kcat/Km = 0.02 lM [92]
Plasma kallikrein FXII 11 lM Km; kcat/Km = 0.57 lM [88]
Single-chain urokinase 0.064 lM Km [22]
High-Mr kininogen 1.4 lM Km; kcat/Km = 0.46 lM [93]
Prolylcarboxypeptidase Prekallikrein 0.007 lM Km [35]
Table 2 Inhibitors of the enzymes of the plasma kallikrein–kinin system independently of HK [22–24]. FXI also binds to prothrombin
Enzyme Inhibitor Inhibition constant+ Reference and the glycoprotein Iba–IX–V complex on platelets [24,25].
Membrane-binding proteins of HK include gC1qR, urokinase
a-Factor C1 inhibitor 222.0 · 103 M)1 min)1 [9] plasminogen activator receptor (u-PAR), and cytokeratin 1
(F) XIIa a2-Antiplasmin 11.0 · 103 M)1 min)1 [9]
(CK1) (Fig. 1) [26–29]. When HK is proteolyzed by plasma
a2-Macroglobulin 5.3 · 103 M)1 min)1 [9]
Antithrombin 1.3 · 103 M)1 min)1 [9] kallikrein or other proteases to form cleaved HK (HKa),
Plasma C1 inhibitor 102.0 · 104 M)1 min)1 [9] membrane tropomysin also functions as a binding site uniquely
kallikrein a2-Macroglobulin 69.0 · 104 M)1 min)1 [10] for this form of kininogen [30]. FXII also has been shown to
Antithrombin 1.8 · 104 M)1 min)1 [10] bind to gC1qR, u-PAR, and CK1 [27,31]. Both PK and FXI
a1-Antitrypsin 0.025 · 104 M)1 min)1 [10]
circulate in plasma almost completely bound to HK, but PK
PAI-1 360.0 · 104 M)1 min)1 [94]
Protein C inhibitor 600.0 · 104 M)1 min)1 [95] binding to endothelial cells predominates [24]. The reasons for
this are as follows: (i) the concentration of PK (450 nM) is more
PAI-1, plasminogen activator inhibitor-1.
+ than tenfold greater than that of FXI (30 nM) in plasma; and
The values are second-order rate constants.
(ii) the free Zn2+ concentration required for PK binding is only
0.3 lM, whereas that for FXI binding is 7 lM [24].
ordering of the adsorbed protein molecules that lead to When HK and PK assemble on endothelial cells and matrix,
expression of its active site [13]. Negatively charged surfaces plasma kallikrein activity arises independently of added FXIIa.
consist of artificial materials as found in coagulation assays such This event occurs in the presence of neutralizing antibody to
as kaolin, celite, and glass surfaces. Several physiologic
substances, such as articular cartilage, skin, fatty acids, endo-
toxin, sodium urate crystals, calcium pyrophosphate, L-homo-
cysteine, hematin, protoporphyrin, sulfatides, heparins,
chondrotin sulfates, and amyloid b-protein, also support
autoactivation of FXII. Formation of activated FXII by
autoactivation results in PK activation with reciprocal activa-
tion of FXII and PK and activation amplification of the system.
In vivo, FXII autoactivation occurs on developing thrombus,
contributing to its extent [7]. Substances that contribute to
Ôcontact activationÕ on a developing thrombus include RNA
from degrading cells, polysomes from platelet membranes, and
fibrin itself [14,15]. FXII activation also occurs under conditions
of sepsis, where bacteria provide a negatively charged surface,
proteases to activate FXII, or a binding site [16,17].
Fig. 1. Physiologic assembly and activation of the plasma kallikrein–kinin
system. The high molecular weight kininogen (HK)–prekallikrein (PK)
Constitutive activation of the plasma KKS in the complex binds to its HUVEC receptor complex, which includes cytoker-
atin 1 (CK1), urokinase plasminogen activator receptor (u-PAR) and
intravascular compartment gC1qR. Prolylcarboxypeptidase (PRCP) bound to the complex activates
It has been recognized that HK, FXII and PK specifically, PK to form plasma kallikrein (KAL). The KAL cleaves HK and acti-
vates FXII and single-chain urokinase plasminogen activator (Scu-PA).
saturably and reversibly bind to endothelial cells, platelets Cleaved HK liberates bradykinin (BK), which is a potent activator of
and granulocytes [18–21]. HK serves as the major binding site tissue-type plasminogen activator (t-PA), NO (nitric oxide) and prosta-
for PK and FXI, although both bind to endothelial cells cyclin (PGI2) liberation from endothelial cells. HKa, cleaved HK.
Ó 2007 International Society on Thrombosis and Haemostasis
3. The changing kallikrein–kinin system 2325
FXII and FXII-deficient plasma, but not PK-deficient plasma
Vascular activities of the plasma KKS
[22,32]. The plasma kallikrein formed results in kinetically
favorable single-chain urokinase activation (Km = 64 nM) Regulation of blood pressure and flow Local BK formation
(Table 1) [22]. The plasma kallikrein on endothelial cells also is known to influence blood pressure. BK is liberated from HK
results in kinetically favorable FXII activation [33]. These data by plasma or tissue kallikrein cleavage. The nine amino acid
provide an alternative hypothesis to contact activation for BK peptide, RPPGFSPFR, has two intravascular receptors:
FXIIa formation in vivo. The increased requirements for free B2R, which is constitutively expressed, and the BK B1 receptor
Zn2+ for FXII binding to endothelial cells suggest that FXIIÕs (B1R), which becomes expressed in inflammatory states. BK
association and activation on endothelial cells follows HK and binds to B2R, a seven-transmembrane G-protein-coupled
PK assembly and activation [24,31]. This proposed mechanism receptor, and stimulates its G-proteins to release nitric oxide
for PK activation in vivo may be occurring constitutively. (NO), prostaglandin I2 (prostacyclin), smooth muscle
Firstly, C1INH knockout mice have constitutive tissue edema hyperpolarization factor, and superoxide [43–46]. In sepsis,
due to increased BK, as it is blocked by a B2R antagonist or by excessive BK release contributes to hypotension.
mating C1INH and B2R knockout mice [11]. As plasma BK BK produced by the plasma and tissue KKS influences
only arises from plasma kallikrein formation and C1INH only cardiovascular physiology. B2R knockout mice are not consti-
inhibits plasma kallikrein, not tissue kallikein, BK must be tutively hypertensive; however, upon being subjected to a salt
constantly formed in vivo to give the paw edema seen [11]. load, they have early-onset salt-sensitive hypertension [47]. B2R
Secondly, FXII knockout mice also have plasma BK formation is involved in the control of regional vascular tone in the coro-
without the presence of FXII [34]. nary arteries and the kidneys. The cardioprotective effects of
A PK activator was purified from endothelial cells [35]. On angiotensin-converting enzyme (ACE) inhibition, which inhibits
amino acid sequencing, it was identified as the serine protease BK degradation, is lost in B2R knockout mice. In diabetic mice,
prolylcarboxypeptidase (PRCP) [35]. The Km of PRCP activa- the absence of B2R increases oxidative stress, mitochondrial
tion of plasma PK (Km = 7 nM) is two hundred and fifty- to DNA damage, and senescence-associated phenotypes [48]. In
three hundredfold higher than that for activated forms of FXII tissue kallikrein knockout mice, with reduced tissue BK
(Table 1). This suggests that PRCP activation of PK is favored formation, there is thinning of the septum and posterior wall
over that of a-FXIIa or b-FXIIa in vivo (Table 1). It is of note of the heart, resulting in ventricular dilatation and reduced left
that C1INH is a tighter inhibitor of plasma kallikrein than of ventricular mass [49]. Furthermore, genetic kininogen deficiency
activated FXII, suggesting that plasma kallikrein regulation is in rats contributes to aortic aneurysm formation [50].
more important than that of FXIIa (Table 2). PRCP was first
recognized as a degrading enzyme for BK and angiotensin II Thrombosis risk Emerging information indicates that the
(Ki 1 and 0.15 mM, respectively) by cleaving Pro-X bonds on plasma KKS influences thrombosis risk independently of
the C-terminus of the protein [36]. Both purified and hemostasis [7,8]. Patients with FXII, PK and HK deficiency are
recombinant PRCP activate PK with a Km 7–17 nM exceedingly rare, and although they do not bleed, there are too
[35,37]. Although thought to be lysosomal in origin, PRCP is few patients to characterize a common clinical phenotype.
a membrane and matrix protein, as it can be demonstrated to be FXII deficiency is more common than HK or PK deficiency.
there functionally and immunochemically and it was interrupted Clinical investigations for venous thrombosis risk or on
by a gene trap targeted to membrane proteins [35,37–39]. PRCP polymorphisms of FXII and their influence on cardiovascular
is a risk factor for metabolic syndrome in men, and a PRCP disease have been conflicting (see below). The clearest
polymorphism is associated with pre-eclampsia in women information on thrombosis risk or risk amelioration has been
[40,41]. CHO cells with overexpressed PRCP have increased derived from animal models, which demonstrate unexpected
PK-activating activity over controls; treatment of these cells findings.
with small interfering RNA reduces the PK activation on these
cells [42]. Finally, transfected CHO cells mostly express PRCP BK and kininogen BK infusion is a potent stimulant for tissue-
on their membranes. These combined studies indicate that there type plasminogen activator (t-PA) release in rabbits and humans
is a constitutive, physiologic endothelial cell mechanism for PK [51]. Kininogen itself has been shown to have antithrombin
activation independent of FXII autoactivation by contact. activities. Both HK and low molecular weight kininogen at 5%
of their physiologic concentrations block thrombin-induced
platelet aggregation and serotonin release by inhibiting
Activities of the plasma KKS
thrombin binding to platelets [52]. The thrombin inhibitory
The studies described above reveal a means for KKS assembly regions of kininogen have been associated with domains 3 and 4,
and activation by physiologic and pathophysiologic mecha- the BK region [53,54]. A peptide comprising the first five amino
nisms. Several vascular and cellular activities derive from these acids of BK, RPPGF, was found to bind weakly to the active site
pathways. KKS vascular activities include regulation of blood of thrombin upon cocrystallization, and to bind the exodomains
pressure and flow and thrombosis risk; the cellular activities of protease-activated receptor (PAR)1 and PAR4 to prevent
include cellular proliferation, growth, angiogenesis, apoptosis, thrombin cleavage [55,56]. RPPGF inhibits in vitro and, when
and inflammation. infused in dogs and humans, ex vivo thrombin-induced platelet
Ó 2007 International Society on Thrombosis and Haemostasis
4. 2326 A. H. Schmaier and K. R. McCrae
aggregation [57,58]. RPPGF in pharmacologic doses prevents binds to the overexpressed angiotensin receptor 2 to increase
carotid artery thrombosis in mice and coronary artery NO and prostacyclin, and prolong the bleeding time of the
thrombosis in dogs [57,59,60]. animal [8] (Fig. 2). Thirdly, RPPGF is elevated in these animals,
As BK induces NO, prostacyclin and t-PA release from due to increased BK degradation by ACE [8]. The elevation of
endothelial cells, we hypothesized that the B2R knockout mouse RPPGF levels may also contribute to the thrombosis protection.
would be prothrombotic. To our surprise, B2R knockout mice These combined studies indicate that BK and its receptor system
have delayed carotid artery occlusion times in the Rose Bengal indirectly influence thrombosis risk by influencing endothelial
model (Fig. 2) [8]. The mechanism for thrombosis protection is cell biology through cross-talk with components of the plasma
dependent on this systemÕs interaction with the renin–angioten- RAS. Such a pathway for risk modification of intra-arterial
sin system (RAS) [61]. In the RAS, angiotensinogen is converted thrombosis has not been previously appreciated.
to angiotensin I by renin and then converted to angiotensin II by
ACE. ACE also is the major enzyme that degrades BK to BK FXII There are conflicts between human clinical and
1–5 (RPPGF) in the intravascular compartment (Fig. 2). experimental animal data for the role of FXII in thrombosis
Angiotensin II usually binds to angiotensin receptor 1 to induce risk. A polymorphism in FXII (46C/T) is associated with
vasoconstriction and salt retention, and elevate blood pressure. increased risk for arterial thrombosis [63–65]. Individuals
However, if angiotensin receptor 2 is overexpressed, angiotensin homozygous for the 46C/T polymorphism have lowered FXII
II will preferentially bind to it to induce vasodilatation and and FXIIa levels. Reduced activated forms of FXII may be
blood pressure reduction. The mechanism by which the B2R associated with reduced total fibrinolytic activity, resulting in
knockout mice are protected from thrombosis is 3-fold. Firstly, increased thrombosis risk. This interpretation is opposite to
in the absence of B2R, angiotensin receptor 2 is overexpressed what is demonstrated in FXII-deficient mice [7]. FXII-deficient
(Fig. 2). B2R and angiotensin receptor 2 colocalize in cells, and mice have reduced thrombus after induction of arterial clots
there is an as yet unrecognized mechanism whereby the presence [7,66]. The mechanism for the increased size of thrombus in
of one GPCR receptor regulates the expression of the other mice that have normal levels of FXII may be related to
[8,62]. Secondly, there is increased angiotensin II as a result of increased contact activation occurring on a developing platelet
reduced BK uptake into cells with reflexive increased ACE thrombus [14,15]. Therapeutic inhibition of FXII may result in
degradative activity [8] (Fig. 2). The increased angiotensin II reduced thrombus formation without bleeding. These
observations were not predicted by in vitro investigations on
the biochemistry and cell biology of FXII and clinical studies
on populations with polymorphisms or defects in FXII.
Cellular activities of the plasma KKS
Cell proliferation and angiogenesis Investigations have
shown that kininogen and related proteins influence cellular
activities of endothelial and other cells. These investigations
were prompted by the observation that HKa induces selective
apoptosis of proliferating endothelial cells and inhibits
angiogenesis [67,68]. HKa inhibits neovascularization of s.c.
planted Matrigel plugs, as well as fibroblast growth factor
2-induced angiogenesis in the chick chorioallantoic membrane
Fig. 2. Mechanisms for thrombosis protection in bradykinin B2 receptor assay [67,68]. Moreover, peptides from domain 5 of HK (D5),
(B2R) knockout mice. In the absence of B2R, there is increased plasma which subsumes the HK cell-binding region, induce endothelial
bradykinin, as B2R accounts for 40% of the metabolism of bradykinin.
cell apoptosis, inhibit angiogenesis, and are antibacterial
Increased bradykinin results in increased conversion to bradykinin 1–5
(peptide RPPGF) (Blood 2006; 108: 192–99). As a byproduct of increased [69–71]. Kininogen-deficient Brown Norway Katholiek rats,
RPPGF formation, there are increased levels of angiotensin II (Blood alternatively, display decreased angiogenesis, possibly resulting
2006; 108: 192–99). Angiotensin-converting enzyme (ACE) also converts from deficient BK release that is ameliorated by a BK analog or
angiotensin I to angiotensin II. In the absence of B2R, there is increased kininogen replacement [72,73]. The mechanism(s) by which
expression of the angiotensin receptor 2 (AT2R). The increased angio-
these activities occur is not known, but may involve the anti-
tensin II is shunted to overexpressed AT2R, as angiotensin II has the same
binding affinity for angiotensin receptor 1 and AT2R. This leads to a adhesive function of HKa towards cells on vitronectin, the
paradoxical effect in comparison to the usual angiotensin II elevation. kininogen multiprotein receptor complex, or tropomyosin
Increased stimulation of AT2R produces vasodilatation and increased [30,74,75].
plasma nitric oxide (NO) and prostacyclin (PGI2) (Blood 2006; 108: 192–
99). The increased NO and PGI2 prolong the bleeding time, and these Outside-in signaling mediated by the KKS Although the
animals have delayed thrombosis risk on the Rose Bengal model for
carotid artery thrombosis. These investigations indicate that thrombosis proangiogenic activities of the KKS are mediated by B1R and
risk can be modified by factors independent of coagulation, fibrinolytic or B2R, a different receptor system(s) may be involved in the
anticoagulant proteins. inhibition of cell proliferation, adhesion, anti-apoptosis and
Ó 2007 International Society on Thrombosis and Haemostasis
5. The changing kallikrein–kinin system 2327
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This work was supported in part by grants HL052779, Esterl W. Activation of the contact-phase system on bacterial surfaces
HL055709 and HL086038 to A. H. Schmaier, and grants is a clue to serious complications in factious disease. Nat Med 1998; 4:
HL076810, CA83134 and P50HL081011 to K. R. McCrae. 298–302.
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