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How do we form plugs to stop blood loss? ex Two mechanisms: Clumping of circulating blood cells and Conversion of whole blood to form fluid gel
What method is good for plugging small holes in blood vessels? Clumping of circulating blood cells
What method is good for plugging a large hole in blood vessel? Conversion of whole blood into gel
How is clumping accomplished? Platelts clump together, Held together by blood proteins, Blood proteins bind to surface receptors of platelets to form non-covalent cross-links
How is conversion of blood to gel accomplished? Blood proteins are polymerized together, Resulting in formation of a network of fibers throughout volume of blood plasma
In both forms of plug formation, what is the associated blood protein? Fibrinogen
What two physiological requirements govern hemostatic response? Response must be fast and complete, And, Response should never occur inside an intact blood vessel
What is formation of a clot inside a blood vessel called? Thrombosis
What is a thrombus? Blood clot formed within a blood vessel
What is a clot that dislodges and travels through the circulation called? An Embolism
What can a slow or incomplete response result in? Loss of blood components, Loss of blood pressure, Damage to surrounding tissue
How do blood vessels and blood prevent thrombosis? Mechanisms in place to inhibit or reverse process of hemostasis
What are cells and proteins that promote blood clotting referred to as? Procoagulant, prothrombotic
What are cells and proteins that inhibit or reverse blood clotting referred to as? Anticoagulant, antithrombotic
There is a balance between ______ and ______ in a healthy individual Procoagulant and anticoagulant
Who are the major players of balancing hemostasis? Platelets, Clotting factos, Serpins, Plasminogen, Endothelial cells and, Subendothelial cells
What are some properties of Platelets? Small, Non-nucleated, Circulate in an inactive form, Activated upon contact with subendothelium, Prothrombotic, Cannot synthesize proteins, Short lived (7-9 days), Metabolically active, but hemostatically inactive in circulation
What are some examples of soluble blood proteins? Clotting Factors, Serpins, and Plasminogen
What are the general properties of Clotting Factors? Circulate in an inactive form Prothrombotic
What are some properties of Serpins? Inhibit clotting factors, Antithrombotic
What are some properties of Plasminogens? Activated to form Plasmin, Plasmin dissolves clots, Antithrombotic
What are some properties of endothelial cells? Inner lining of blood vessel, Antothrombotic
What are some properties of subendothelial cells? Outer layer of blood vessel, Activates platelet and blood coagulation upon contact, Prothrombotic
What is the trigger form blood clot formation? When platelets and clotting factors come into contact with subendothelial cells
What is responsible for initiating the activation of plateles? Collagen (component of subendothelial cells)
What is responsible for initiation the activation of clotting factors? Tissue factor and Collagen (components of subendothelial tissues)
External trauma to blood vessels results in... Triggering a massive activation of platelets and clotting factors
Internal trauma to blood vessels results in... Limited local activation of platelets and clotting factors (in response to mechanical stress, high bp, hyperlipidemia or oxidative stress)
What are the 3 processes involved in the hemostatic response? Platelet Aggregation, Vasoconstriction, and Blood coagulation
What does platelet aggregation result in? Formation of a platelet plug and, Stimulation of vasoconstriction and blood coagulation
What are some properties of platelet aggregation? Very fast, Formation of fragile platelet plug, Plug consists of platelets crosslinked with a few porteins, Excludes most of the volume of blood, Stimulates vasoconstriction and blood coagulation
What are some properties of vasoconstriction? Very fast, Reduces blood flow, Promotes platelet aggregation and blood coagulation
What are some properties of blood coagulation? Slow, Formation of durable clot, made of polymerized blood proteins, Involves entire volume of blood, Blood transformed from fluid state to a gel state
What are the properties of Inactive platelets? Surface Receptors for platelet activators (Collagen, Thrombin, TXA2, and ADP), Round and smooth, Lots of secretory granules, and Surface receptors for platelet inhibitors
What does bind of Collagen Thrombin
What does binding of PGI2 to an inactive platelet result in? G-protein linked receptor coupled to adenlate cyclase, Prodcution of cAMP ensues, (eg phosphotidylserine) become exposed on outer leaflet of cell surface) Which inhibits release of Calcium, thereby antagonizing platelet activation
What does the change of phospholipid expression upon platelet activation provide? Specific platform for assembly and activation of blood coagulation factors
What can the receptors of an inactive platelet bind too? Collagen, TXA2, Thrombin, ADP, and PGI2
What can the surface receptors of an activated platelet bind too? Fibrinogen and Von Willebrand factor
What determines whether a platelet will be acticated? Balance of positive signals from collagen, ADP, TXA2 and thrombin versus negative signal from PGI2
What is the sequence of events leading to the formation of a platelet plug? 3 A’s: Adhesion, Activation and Aggregation
What happens during adhesion? Process occurs instantaneously, A few inactive platelets bind to collagen of exposed subendothelium, Results in immobilization and activation of platelets
What happens during Activation? Occurs in a fraction of a second, Immobilized and activated platelets secrete and release ADP and TXA2, Resultant of which is activation of neighboring platelets, Creation of a cascade effect
What happens during Aggregation? Fibrinogen and Von Willebrand Receptors unmasked, Fibrinogen, which is a common blood protein, has two binding domains on either end, So, fibrinogen literally sticks platelets together tightly, Resultant of which is excellently, non-covalent cross-li
How long does it take for the recruitment of platelets to platelet plug to begin? Fraction of a second
What is thrombocytopenia? Not enough platelets
What is Clanzman’s Thrombasthenia? Defective fibrinogen recetpros
What are platelet deficiencies usually associated with? Appearance of petechiae (multiple small reddish or purplish bruises)
What is the dual role of platelets? Role in hemostasis and role in wound healing (attraction of neutrophils, macrophages, and fibroblasts to wound site)
How long does it take for clot (secondary) formation to begin? About 30 seconds
Formation of a secondary clot is initiated… Independently of platelet aggregation Though, its formation is stimulated (and accelerated) by the presence of activated platelets and the platelet plug
What happens in response to platelet aggregation?
How is fibrinogen activated and what is the end result? Activated by proteolytic cleavage, Results in removal of small peptides (fibrinopeptides), which ultimately unmasks sites for binding of other fibrin molecules, Resultant of which is formation of a long fibrin fiber (due to binding of fibrin monomers to
What causes formation of a clot during blood coagulation process? Aggregation and (covalent) cross-linking of Fibrin blood proteins
What is fibrin? Activated form of fibrinogen (fibrinogen is known as clotting factor 1 or F1), Also known as “Clotting Factor 1a” or F1a, Is the most abundant of the clotting factors in the blood
What catalyzes the cleavage of fibrinogen to fibrin? Thrombin
Thrombin: Secrete as inactive prothrombin (prothrombin also known as Factor II) Also known as clotting factor IIa (or F IIa)
How can thrombin be activated? Intrinsic or Extrinsic pathways
What are some properties of the Extrinsic Pathway? Triggered by Tissue Factor (aka extrinsic factor), Function is to INITIATE thrombin activation
What are some properties of the intrinsic pathway? Triggered by negatively charged surfaces (eg Collagen) Function is to AMPLIFY thrombin activation
What occurs during the final steps of blood coagulation (also known as common pathway) ? Activation of prothrombin, Activation of fibrinogen, Aggregation and cross linking of fibrin
What can act as a feedback activator of both extrinsic and intrinsic pathways? Thrombin
Why is thrombin dangerous? Because it can act as an activator of both intrinsic and extrinsic pathways, Thus, a few molecules of active thrombin can trigger RAPID formation of a fibrin clot
What are all clotting factors activated by? Proteolytic cleavage
What are many clotting factors converted into? Serine proteases
Which clotting factors are not zymogens? 5, 8, and fibrinogen
What is clotting factor 13? Zymogen, transamidase
Which clotting factors are serine proteases? Prothrombin, 7, 9, 10, 11, & 12
What are some properties of serine proteases? Similar catalytic sites, with serine present, Related to serine proteases involved in digestion (eg trypsin), Similar amino acid sequences in parts of polypeptide near catalytic site, Exceptionally different amino acid sequences everywhere else, Bi
What gives serine proteases unique substrate specificity and a unique position in the clotting cascade? Fact that they each bind substrates of specific shapes, exclusively, And, Fact that other than catalytic site, amino acid sequences are quite different from one another
What is the only thing that factor 11a will cleave? Factor 9
What will only factors 9a and 7a cleave? Factor 10
What will only factor 10a cleave? Prothrombin
How is thrombin different from other clotting factors? Has a broader specificity
What can Thrombin cleave? Factors: 13, 11, 8, 7, 5 and Fibrinogen as well
What is the sequence of thrombin activation (and blood clot formation) ? In presence of tissue factor, F7a activates F10 (only small amount of F10a formed), F10a activates small amount of prothrombin to thrombin, Thrombin activates: F13, F11, F8, F7, F5, and Fibrinogen, Factor 11a activates F9, In presence of F7a, F9a act
What constitutes the extrinsic pathway? In presence of Tissue Factor, F7a activates F10
What constitutes the intrinsic pathway? Thrombin activates: F13, F11, F8, F7, F5, and FibrinogenF11a activates F9a In presence of F7a, F9a activates large amounts of F10
What constitutes the common pathway of coagulation? F10a activates small amount of prothrombin, Large amounts of F10a make large amounts of thrombin, Large amounts of thrombin activate all fibrinogen and F8, Fibrin polymerizes, F8a crosslinks fibrin network
The first step of thrombin activation (F7a activates small amount of F10) occurs only when…? Blood comes into contact with the subendothelial tissue’s Tissue Factor (TF) TF is a membrane protein only found on subendothelial cells
Step 1 is… self limiting, Each molecule of F7a produces only a few molecules of F10a before it completely shuts down
What does F7a do as soon as it binds to TF? Recruits blood protein known as Tissue Factor Pathway Inhibitor (TFPI), which inhibits F7a by preventing F10a from dissociating
What do three of the reactions of the clotting cascade that occur on the surface of cells require? Presence of Calcium and Phospholipids, plus a protein coo-activator
Which 3 reactions of the clotting cascade have special requirements? Activation of: F10, Prothrombin, and F7
What does the presence of phospholipid and Calcium due to the affinity of enzyme 9a for its substrate 10? Km of 9a decreases by about 5,000 fold, Thus, affinity increases substantially
What requires Calcium? F7a, F9,a and F10a, as well as Thrombin
What does Calcium help accomplish? Helps F7A, F9A, and F10a bind to negatively charged phospholipid on cell surfaces
What happens in the absence of Calcium? Clotting does NOT occur, (hence why Ca chelators are such effective inhibitors of blood clotting)
What are some examples of effective chelators? EDTA and Citrate
When are chelators not useful? As clotting inhibitors in vivo
What do clotting factors that bind Calcium all have? Modified gama-carboxyglutamate at several different positions (modified amino acid), Added post-translationally
What is maturation? Post-translational process whereby amino acid is modified to gama-carboxylglutmate in the Liver by way of enzyme gama-glutamyl carboxylase, Must take place in cell before clotting factor is secreted into blood
What happens if immature clotting factor is secreterd? Can undergo proteolytic cleavage, But cleavage product will not be active because it cannot bind Calcium
What is the most severe and common of the hereditary blood clotting disorder? Hemophilia A, Due to deficit in clotting Factor 8 What causes hemophilia B?
What can Factor 12a do? Activate Factor 11 and initiate intrinsic pathway, Role in inflammatory response and stimulates fibrinolysis, Is itself activated by negatively charged surfaces, such as glass, dirt, or collagen
What happens if a patient lacks Factor 12? Normal bleeding in vivo
Created by: qcom12



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