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63 Cards in this Set
- Front
- Back
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What does hemostatsis involve?
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-Blood coagulation
-Fibrinolysis (of fibrin clot) -Repair of vessel wound |
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What activates hemostasis?
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-When endothelial cells are damaged
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What are the two triggers?
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1. Exposure of collagen in the subendothelium (triggers platelet plug formation)
2. Tissue surface factor (triggers fibrin clot formation) |
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What is primary hemostasis?
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Platelet plug formation
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What is secondary hemostasis?
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Fibrin clot formation
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Sequence of events after damage to vessel wall
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1. Adhesion of platelets to collagen
2. Increase of intracellular Ca2+ to activate platelets 3. Platelet degranulation and secretion of platelet agonists 4. Shape change 5. Aggregation of platelets to one another |
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What is von Willebrand Factor?
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-It is a linker protein found in blood that binds to collagen. It causes a conformational change that allows vWF to bind to platelet integrin GPIb
-It anchors the platelet -Fxns in both primary and secondary hemostasis |
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What does a decrease in vWF do?
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-Decrease in adhesion of platelets
-Increased turnover of factor 7 |
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What is the goal of platelet adhesion?
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Culminates in a monolayer of platelets adhering to the wound site; collagen can also directly contribute to platelet adhesion by interacting with platelet integrin GPIa/IIa
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What are some platelet agonists?
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-Thrombin
-Thromboxane A2 -ADP -Epi -Collagen |
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How do platelets get activated?
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Agonists triggers an increase in intracellular Ca2+ conc
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What is the result of platelet activation?
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Granule secretion, shape change, aggregation
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What are eicosanoids?
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-Signaling compounds made from omega-3 and omega-6
-They act as autocrine and paracrine signaling compounds involved in immunity and inflammation |
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Which eicosanoids are important in hemostasis?
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-Thromboxane A2: produced by platelets to promote platelet plug formation
-PGI2: produced by intact vessel wall to inhibit platelet plug formation |
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What does cyclooxygenase do??
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It catalyzes the first commited step in PGI2 and TXA2 biosynthesis
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What are some examples of cyclooxygenase inhibitors?
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-ASA
-APAP -Ibu -Celebrex -Steroids |
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What is TXA2's MOA?
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Recruits additional platelets to form the platelet plug. It is inhibited by ASA.
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What is Plavix's MOA?
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Binds to ADP receptors and prevents ADP from promoting platelet plug formation.
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What is released by platelets during degranulation?
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1. Stored platelet agonists
2. Clotting factors 3. Growth factors 4. Adhesive proteins 5. Serotonin to aid in vasoconstriction |
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What is the role of the platelet's membrane during hemostasis?
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Provides a site for clotting factor binding
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How do plalelets aggregate?
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By fibrinogen binding to active GPIIb-IIa on two different platelets. Fibrinogen is a long fibrous moleucle with two identical halves. Each half is recognized by GPIIb/IIIa; these two binding sites allow one fibrinogen molecule to bind 2 platelets.
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What inhibits platelet plug formation on intact vessel walls?
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1. Charge of endothelial cells
2. ADPase hydrolyzes ADP, preventing further platelet activation 3. Secreted compounds |
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What secreted factors inhibit platelet plugs?
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-Prostacyclin PGI2
-NO: lowers Ca2+ inside cell |
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What do platelets do in hemostasis?
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Platelet activation leads to promotion of platelet plug and fibrin clot formation via a positive feedback mechanism.
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What is an extrinsic clotting factor?
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Tissue factor 3
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What are intrinsic clotting factors?
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Anything that is circulating in the blood
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How are clotting factors activated?
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They undergo limited proteolysis by a particular activated protease in the coag system
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What are the 3 complexes anchored in the membrane?
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1. Initiation complex
2. Tenase complex 3. Prothrombinase complex |
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How does coumadin/warfarin work?
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They are vit K analogs and competitively inhibit the carboxylation of Glu to Gla. They are anticoagulants.
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What does Ca2+ do?
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Serves as a bridge between the Gla residues of activated clotting factors and the membrane phospholipids of the activated platelets. This localizes the enzymes for clot formation. Acts as a check on the coag cascade.
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What is the principal means of initiating the coag cascade?
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Exposure of TF3. Factor 7a binds TF3 via Ca2+ to form the initiation complex.
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What does the initiation complex do?
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When bound to TF3, it catalyzes the limited proteolysis of additional factor 7, 9, and 10. 9a and 10a are the two proteases use to from the other 2 complexes in coag.
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What does tenase complex activate?
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Factor X
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What does prothrombinase complex activate?
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Factor 2. Prothrombinase creates thrombin which is the enzyme that cleaves fibrinogen to fibrin.
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What does fibrin do?
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Spontaneously polymerizes to form the fibrin clot. Initially it is held together by only ionic bonds so its a soft clot.
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How does the soft clot convert to the hard clot?
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Fibrin also catalyzes the conversion of factor 8 to 8a. 8a is fibrin stabilizing factor and it forms peptide bonds between lysine and glutamine which makes the clot more resistant to degradation.
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What accelerates coags?
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Thrombin by activating factors 8,5, 9.
It also binds to its receptor on platelets to accelerate platelet activation. |
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What limits coag?
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Heparin sulfact forms a complex with ATIII increasing the effectiveness 1000 fold
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What do proteins C and S do?
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Protein C is converted into activated protein C. Together with protein S, they deactivate factors 5a and 8a into their inactive forms.
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What does tissue factor pathway inhibitor do?
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Turns off the extrinsic pathway by binding to Xa and 7a while they are bound to TF3.
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What is fibrinolysis?
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Removal of the clot as part of wound repair.
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What initiates fibrinolysis?
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tPA from endothelial cells. It degrades fibrin and cleaves the peptide bonds.
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What factors inhibit platelet plug formation?
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PGI2, NO, ADPase, APC, TM, heparin
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What is the drug of choice for arterial clots?
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ASA
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What is the drug of choice of venous clots?
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Heparin
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What color are arterial clots?
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White, because they are rich in platelets
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What color are venous clots?
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Red because they are rich in fibrin which captures RBCs
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What are some fibrinolytics?
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tPA, streptokinase
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How does heparin work?
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It provides a binding site for the ATIII (an endogenous anticoagulant) to bind in close proximity to thrombin. This inhibits clot formation.
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Which clotting factors does coumadin work on?
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7, 9, 2, and 10. It acts by inhibiting fibrin clot formation. Act through the liver instead of the inj site.
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How is platelet fxn determined?
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Bleeding time
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How is clot formation assessed?
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-aPTT
-PT -Clot solubility in 5M urea |
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What does 5M urea do?
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Dissolves soft clots but not hard clots. If the clot dissolves, then there is no 8
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What prolongs bleeding time?
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ASA, vWF dz, thrombocytopenia
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What dz is responsible for a deficiency in GPIb?
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Bernard-Soulier
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What factors does PT test?
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7, 10, 5, prothrombin, fibrinogen
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What does the PT test measure?
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The time it takes a sample of citrated plasma to clot upon addition of Ca2+ and purified tissue factor. It bypasses the intrinsic factor; tests only extrinsic and common.
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What does the aPTT test?
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The intrinsic and common pathway. Used to screen for acquired/inherited deficiencies of 12, 11, 9, 8
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What does a prolonged aPTT test suggest?
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-Deficiency or structural defect in one or more of the factors in the intrinsic/common pathway (1, 2, 5, 11, 9, 10)
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What causes hemophilia A?
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Deficiency in factor 8
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What causes hemophilia B?
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Deficiency in factor 9
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Which clotting factors are vitamin K dependent?
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7, 9, 10, 2
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What inhibits coagulation?
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ATIII
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