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213 Cards in this Set
- Front
- Back
What is hemostatis
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arrest of bleeding or clot formation on following vacular injury
|
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What are key players in hemostatis
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1. Plateltes
2. Coagulation cascade 3. Blood vessels |
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Hemostatis involves a sequence of events designed to restore vascular integrity---what 5 are they
|
Vascular constriction
Formation of Platelt Plug Activation Clotting casacde Formation of Blood Clot Clot Dissolution |
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Do all 5 steps occur simultaneously within vasculature
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YES
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What is vascular constriction
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damage to vessels releases meditors which cause vasoconstriction and limit blood flow
|
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What are 3 main steps of formation of platlet plug
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platlet adhesion, activation and aggreation
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What does the normal endotherlal cell produce that results in a resting platlet
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NO, and PGI2
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However after vascular damage, what is exposed that allows platlets to bind
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exposure of collagen and von willebrand factor which help the platelt adhere to site of injury
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After platlets adhere to site of injury they are activated, releasing
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ADP, TXA, EPI, which causes a conformation change in platlets, leads to aggregation
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After aggregation--form platelt plug, if this damge in the blood vessel is small, what happens
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the platelt plug itself can stop blood loss
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Platelt plugs seals minute ruputres, but if thre is a larger area of damage, is what is also require
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blood clot
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What activates clotting cascade--(instrinsic and extrinsic)
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when vascular injury occurs and collagen is exposed the endothelium releases tissue factor which activates
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There is no clinical differeance between intrinsic and extrinsic patway, both lead to production of
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activation of Factor Xa
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Factor 10a leads to formation of Thromibin is KEY for produces
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fibrin, feedback amplication, and platelt activation
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Fibrin is needed for
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stable blood clot
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What are Vitamin K dependent factors
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2, 7 9,10
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What are activated factors which are inhibited by heparin or antithrombin III
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Thrombin
Factor 10a Factor 9a Factor 11 and 12a |
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Clotting cascade is a series of enzymatic reactions and do clotting factors circulate in inactive form
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YES
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Clot dissoluation works by fibrinolytic system, what happens
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you have circulating plasminogen, and when exposed to tpa or upa (producd by body), is converted to plasmin, which cut fibrin
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Plasmin cuts fibrin leading to
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clot dissolution
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What prevents blood clotting in the normal healtly vascular system
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smoothness of endotherlium
negative chagne of protein in the endothelium |
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Damage to the endothelium destory the smooth of endotherlium and the negative cahnge--this distruption may lead to
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distruption of hemostatis
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What 3 componetes contriubtes to hemostatic balance
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vessel
circulating elements blood flow |
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What are thrombogenic factors in vessel wall
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DPT
damaged endolieum tissue factor Plasminogen activtor inhibitor (inhbiit TPA/upA) prevent fibrionylsis |
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What are circulating elemetns that are thrombogenic
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platelets, clotting factors, fibrinogen, and von-willibrand factors
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What type of blood flow is thromogenic
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slow or turbelt blood flow is thrombogenic
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Wht are ANTIcoagulant factors in vessel wall
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heparin sulfate
thrombomodulin TPA-upa |
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What are anigcoagulatnts factors in ciruclating elements
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AT
protein C/s plasminogen Tissue factor pathway inhibtor |
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What type of blood flow is anticoagulatnt
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rapid rate of flow, laminar flow
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Inhibitors of clotting factors help to
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localoze the clotting process, and prevent abmnormal clot formation in circulating blood
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Anticoagulation in vessel wall is Heparin, Thrombomodulin, and Tpa/Upa
What is Heparain |
accelerate anti-thrombin
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What is Thrombomodulin
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modulates thrombin by activing protein C
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Circulating factors that are anticoagulatant AT, Protein CS and Plasminogen TFPI, what is Protein C/S
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Protien C--inactiosn factors 5a and 8a
Protein S--cofacotr for active of protein C |
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What 2 things active protein C
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Thrombomodlu,, and Portein S
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What is TFPI (tissue factor pathway inhibitor)
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inhibits activity of Factor 7a by bindin to tissue facotor
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What is role of plasminogen activator inhibitor
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inhibits formation of plasmin
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What is role of plasmin
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lyses fibrin
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What are disorders of clotting
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venous thromboembolicm, MI, Stroke, PAD
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What disordrees of bleeding
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Vit K deficiceny
hemophilia thrombocytopenia |
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Noraml Platelet count
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150,000-400,000
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Platlets <150,000
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thrombocytopenia
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Platelets >400,000
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thrombocytosis
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What is half-life of platelets
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10 days
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What is a thrombosis
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pathologic process leading to inappropriate clot formation
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What is a thomBUS
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patholoigc clots (is the clot) is staonatry or adheres to vessel wall
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What is an embolous
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intravasular clot that breaks off and floats in the blood and travels until it comes to apoint that is smaller than itself, and loadese in vaculatues
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Characteric of Aterial vs venous clot (color)
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aterial--white thrombi
venous clot red thrombin |
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What are aterial clots composed of
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plateltss
|
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Where do aterial cots form
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area of rapid blood flow
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Where are aterial clots
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usually at the site of vascular injury
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What are venous clots composed of
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fibrin and RBCs
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Where do benous clots form
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low blood flow
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Where are venous clots typically result from
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statis and bascular injury
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What is Vircho's triad--generally
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causes of inappropriate clot formation
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What are 3 main causes of inapproaite clot formation
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1. Venous statis
2. Vascular damage 3. Hypercoagulability |
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What are examples of venous statis
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bed rest/immovilizatoin
LVD, HF tumor, obestity pregnacy |
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What are examples of vacular damage
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AASHITC
Surgery Heart Valve disesase/replacement atheosclerosis MI, Inflammatory disotrtion chemotherapy |
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What are examples of Hypercoagulability
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Protein C/S deficiency
Antithrombin III deficieny Estrogen Pregalancy Inflammation disorder |
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What does pregnacy cuase
|
venous statis, hypercoagulability
|
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What are thrombophilias
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(hypercoagualble conditions)
|
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Thrombophilas are often genetic in nature, what is work up for thrombophilia
|
thrombosis at early age
VTE w/ family history reccunet VTE, or unexplained spontaneous aborption |
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Most common Acquired hyper-coaguable disorder
|
Antiphospholipid antibody syndrome
|
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What are causes of Antiphospholipid antibody syndrome
|
phenytoin, hydralize, andprocainaminde
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What is the most comon inherited disoerder for hypercoagaublity)
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Acitvated Protein C ressitance--
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What does Activated Protein C resistance cause
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venous clot
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What is Protein C/S deficiency
|
vitamin K depends, C inactaion factor V and VIII
|
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Elevated levels of homcytemisemia are know to be raks for for
|
aterial and venous thrombosis
|
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Antithrombin Deficiency normally
|
inctive thrombin and other serine protease
|
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What does Prothiombin Gene mutation G 20210A do
|
increae prothrombin activity and levels--increase risk for clot
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Vita K is necessary for syntheisis of activated clotting factors, and
|
,2,7,9,10 and protein C and protein S
|
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Vit K deficiney causes a decrease in ciruclating functional clotting facotrs, treatment is
|
replaciemnt which requires 12-24hrs for body to make new clotting facotrs
|
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What is actue treatment for Vit K deficiney bleeding
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administered Fresh frozen plasam which replace clotting factor immediaelty
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In liver disease is causes a decrease in ciruclating clotting factors which increase risk of bleeding
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YES
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Hemophilia is due to deficient production of what clotting factors
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Factor 8, and Factor 9
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Thrombocytopenia, bleeding will not occur until platelet count is
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<50,000
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Spontanous bleeding will not occur until platelyt count is
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<20,000
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Ingerited thromboyctyopenia is rate, most are acuired due to
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infectoin
serious illness or drug induced |
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Von Willebrand factors is release from the endothelium and is involved in
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adhesion of platelts to damaged endothelium
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Von Willberbrand factor is responssbile for carrying factor
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VIII, and preventing degreadtion
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Hemostatis involves mechanisms concerned with
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maintenance of blood vessel patency after injury and preservation of blood fluidity
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What are 2 homstatic process
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primary hemostatis and secondary hemoststis
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What is primary hemostatis
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adhesion and accumulation of platlets at site injry forming a platelt plug
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When there is vessel damage there is collagen exposed what do this does
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activation platetles, granule chagre releasing ADP and serotin, and TXA
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Release of chemical medicators ADP and serotonin does what
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activation for more platelts and aggregation, and leads platlet plug
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What is secondary hemostatis
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activation of cogaulation cacascade forming a thrombus
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IS the coagulation system a sequential proteolytic cascade, Aka amplification resposne
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YES
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The convertsion of the extrinsic and intrinsic pathways are
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Xa
|
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What does factor 10a do
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converstions prothombin II, to thrombin IIa
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Thormbin(IIa) is most important for
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converting fibrongoen to SOLUBLE fibrin
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How is a stable clot formed
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factor 13a
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How does factor 13a form a stable clot
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cross linking fibrin
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What clotting factors does thombin activate
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5,8 and 13a
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How is clot formation terminated
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by protease inhbition through anti-thrombin III (it binds to thrombin and inactivates it)
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What does fibrinolysis involve
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the formation of plasmin from plasminogen
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What 2 factors convert plasminogen to plasmin
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TPA and UPA
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What is TPA
UPa |
tissue plasminogen activator, urinary plasminogen activtor
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Where is tpa secreted
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by endothelial cells,
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Tpa is the more important vascular activator its enzymatic activity is increased when
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bound to fibrin--as a trip moelcular complex
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Tpa binds to plasminogen forming plasmin, then plasmin binds
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to fibrin via lysine binding stie leads to clot degration
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A-2 antiplasmin binds to plasmin via
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lysine binding site
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Why must alpha2 antiplamin bind to lysine binding sites
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plasmin bound to fibrin via lysine binding sites is protected from inhibition
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What is fibrinolysis regulated by what protease inhibtiors
|
plasminogen activarot inhibitors 1 and 2 and alpha antiplasmin, which inhbit tPA and uPA
|
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What is real benfit of antiplasmin to it is limits
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inhibits free circulating plasmin
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What happens if plasminogen activator therapy causes massive production of plasmin
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if plasmin exceed >alpha 2 antplasmin, then excess can lead to systemic lytic state
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What do antigoaglant agents do in general
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preven blood coagulation by interfering with the coagulation cascade
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Heparin is a heterologus mixture of mucopolysaccharides derived from
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bovine lune of porcine intestines
|
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Hepatin acts by binding
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with high affinity to antithrombin III, inhibts IIa best
|
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After heparin binds to ATIII, what happens to active site of ATIII
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active site becomes more acessible, and increases ATIII activity 1000x
|
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Anti-thormbin III inhibits
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thormbin (BEST ONE ONLY) and factors 9a, 10,11, 12
|
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ATIII enzyme when boundto heparin better binds thormbin and factors 9a, 10a, 11a ,12a better causing inhibiton
|
of coagulation by prevention of fibrin formation
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Low molecular weight heparins size,and suffix
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4000-6000MW and parin
|
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Examples of LMWH
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enoxaparin, dalteparin, tinzaparin, ardeparin
|
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LMWH has a tail that is
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<16 monosaccharids units
|
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LMWH have a tail <16 monosaccharide units, when means
|
not long enough to bind thrombin better inhibits Xa
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LMWH still can active ATIII, XA inbhition is maintained but you have a decrease
|
IIA inhibiton(thrombin)
|
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What is benefit of LMWH only inhbition Xa
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less bleeding, increased half life and decreased platlet effects
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LMWH do NOT prolong aPPT--when do you monitor aPPT
|
heparin
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How do you administer heparin and LMWH
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iv or sub q---im will give a bruise
|
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aPTT is used fro standard heparin dsoage adjustment, not
|
LMWH
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Major SE's considerations with Heparin and LMWH
|
BOOAT
Bleeding oseoproosis ocassical hyperkalemia allergia reactions thrombyctopenia |
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The is a increase risk of blleding in
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elderly women
pts with renal failure platelet dysfuction |
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Heparin/LMWH are contraindicated in pts with
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active GI blleding recent sugrey CNS trama, hemophilia
|
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Thrombocytopenia is more comon with heparin b/c it is
|
from bovine lung than porvine intestine
|
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Thrombocytopenia involves heparin binding to
|
PLT factor 4
|
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Severe hepain induced thrombyctopenia heparin bind PLT factor 4 and creates
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anti-platlet antibodies--destorying platelts
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Does hperain corss placental barrier
|
can be used for anti-coagulation in pregant women
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What are 2 ways excessive anticoagulation induced heparin can be reversed by
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1.D/C
2. protamine |
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Protamine is a basic peptide isolated from fish sperm, what is MOA
|
bind to heparin and inactivates
|
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Protamine is less effective against
|
LMWH
|
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Protamine should be infused slowly b/c
|
high doses ALSO exert anti-coagulation activity making matter worse
|
|
1mg protamine=
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100 U heparin (neutralize)
|
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What are examples of pentasaccharides
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fondaparinux, and idraparinux
|
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Fondaparinux and idraparinux are long acting, and synthetic
|
pentasaccharis to they bind to ATIII and activate it
|
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Fondaprinux and Idraprinux are selective inhibtion of
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factor Xa----no effect on factor IIa--inhibit coagulation
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How is fondaprinux administered
|
sub-q
|
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No monitoring aPPT with fonadparinux--but be careful with
|
increased risk of bleeding and renal clearance
|
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What are ATIII-INDEPEDNET thormbin ihbitiors (inhibit thrombin withOUT ATIII
|
Hirudin, lepirudin, bilvaruind, aragtroban
|
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ATIII independent thrombin inhibtiors (from leeches) work by
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blocking active site of thromin and decrease thrombin activity, inhibting cogation
|
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Advanages of using ATIII independent thormbin inhibitors bilvauridn, hirudin, is
|
good for ATIII deficient pts
and does not affect plalet or need cofactor ATIII |
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How is ATIII independtin thombin inhibitors given
|
IV
|
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Monitoring for bilirudin,
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aPTT, risk of bleeding and antigenicity(hirudin) (comes from leeches)
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MOA of drogrecogin alfa
|
recombinant form of activated anticoagulaant C
|
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What does drotecogin alfa do
|
active anticoagulation C, which decrease Va and 8a--leading to decrease thormbin and Xa activity
|
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What are are vitamin K antagoinsts
|
warfarin, anisindione
|
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What is MOA of warfarin
|
vitamin K epoxide reductase and vitamin K reducase
|
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If wargarin and anisindione inhibit vitamin K epoxide reducdase and vitamin K reductase then
|
vit K is trap in the oxidzied form
|
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Vitamin K is only active in the
|
reduced hydroxylated or hydroquione form
|
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In essense warfarin decrease formation of active vit K, leading to
|
decrease vit k depend factors which are are need for clotting
|
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What is the anticoagulant of chocie for long-term treatment and prevention and why
|
wafarin becue oral activyt and long half life (40)
|
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How is warfarin monitored
|
INR (international normalized ratio)
|
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What are warfarins major PK interactions
|
99% bound to albumun
meatbolized by hepatic microsomal enzymes vitamin K availability |
|
Is wafarin contraindicated in pregnacy
|
YES
|
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The anticoagulation effects of warfarin can be reversed by
|
discontinuation
or by vitamin K +- factor 9, or fresh-frozen plasma |
|
B/c wafarin is 99% protein bound it can be displaced leading to
|
increased anticoatgulation
|
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Wafarin is metabolized by hepatic microsomal enzymes which can cause
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induction--decreae anticoag
inhibtion--increases anticoag |
|
How do antibiotics affects vitamin K avaialbility
|
GI bacterai synthezie vitK--antibiotic kill vitamin K---leading to increased anticoagluation
|
|
How do leafy green veggies affect Vitamin K
|
decreases anticoagulation
|
|
Inhibition Vitamin K--inhibits factors 2,7,9,10 and
|
anticoagulant C and S
|
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What is signifgant about wafarin ihhibiting ANTI-coagulant C and S
|
may see prothrombotic effect during 1st few days of therapy
|
|
Why is a prothormbic effect seen 1st few days of therapy
|
due to short half-life of anti-coagulatnt C
|
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How is temporary prothrombotic activity of wafarin overcome
|
1st few days use heparin with warfarin
|
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Warfarin may also cause a purple toe syndrome--located and when develop
|
painful, blue-tinged toes, and plantar surface that may develop 3-8 weeks into therapy
|
|
What are examples of ATIII indepdent Xa inhibtiors
|
apixaban, and rivaroxaban
|
|
Apixaban and rivaroxaban MOA
|
selective ihbitiors of Xa--inhibiton of coagulation
|
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What is the therapeutic objective of thrombolytic agents
|
prmotes clot break down through fibrinolysis--restablish blood flow
|
|
When must thrombolytic therapy be instituted
|
soon after occurrence of symptoms--b/c fibrin b/c more corss linked and it is harder to degrade
|
|
Can occulsion of cornary atery can cause
|
MI or ischemia
|
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What was 1st thrombolytic agents
|
streptokinase
|
|
What is stretokinase extracted from
|
hemolytic steptococci
|
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MOA of stretokinase
|
forms a stable 1:1 complex with plasminogen--causing a conformational change to form plasmin--plasmin degrades fibirin
|
|
SEs of Streopkinase
|
blleeding-
allergic reactions--due to antigenticty neutralizing antibodies |
|
What are neutralizing antibodies with streptokinase
|
pts who had a prior steptococcal infection, may make antibodies againsts strep--rendering the drug ineffecitve
|
|
What is MOA of anistreplase
|
acts by binding to fibrin and undergoing deacylation
|
|
Anistreplase binds to fibrin and undergoes deacylation (SLOW)--conversion fo plasminogen to plasmin---and leads to
|
clot lysis
|
|
What makes anisreplase WAY BETTER than stretokinase
|
more clot selective b/c binds to fibrin
|
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What is MOA of urokinase
|
acts by binding plasminogen and converting to plasmin--and degregation of clot
|
|
How is urokinase administered
|
iv--
|
|
SEs of urokinase
|
bleeding, liitle or no fibrin speciificty and alpha antiplasmin depletion
|
|
What is the most selective thrombolytic agent
|
Tissue plasminogen activator (TPA)
|
|
MOA of TPA
|
binding fibrin AND plasminogen to form a trimolecular comples, formins plasmin, have clot degration
|
|
How is TPA administered
|
IV
|
|
What are NEWER plasminogen activator
|
lanoteplase
tenecteplase reteplase |
|
Which plasminogen activator has shorter half-life than tpa
|
reteplase
|
|
Benefits of lanoteplase and teneteplase
|
longer duration of action--no need to infuse continously like tpa, single injection ok
|
|
What are therapeutic uses of plasminogen/plasmin inbhitiors
|
prevent excessive fibrinolysis
|
|
What is an Plasminogen/plasmin inhibitition
|
aminocaporic acid
|
|
MOA of aminocaprioic acid
|
binds to plasminogen and plasmin via lysine binding BLOCKING plamsin binding to fibirin
|
|
Aminocaprioic acids has been used in
|
tooth extraction and after prostate surgery in hemophiliacs
|
|
What are antiplatelt agents
|
Aspirin
Purinergic receptor antagoinsts Glycoprotein IIb/IIIa inhibtiors |
|
Aspirin MOA
|
irrversible inhibitor of COX leading to decrease formation of Thromboxane A2, and decrease pletlat aggreation
|
|
What are purinergic receptor anatagonists
|
ticlopidine, clopidogrel
|
|
Ticlopidine, and clopidergrela are pro-drugs which are converted to
|
active metabolites
|
|
MOA of Purinergic receptor antagoinsts
|
ADP receptor antagoinsts--preventing ADP platelt aggretion
|
|
Ticlopdinea nd clopidogren have slot onset of actions, thus
|
loading dose may be needed
|
|
Major side effects of ticlopdine, why its generally not use
|
neutropenia, and thrombocytopenia puppra TTP
|
|
What are Glycoprotein IIb/IIIa inhibitors
|
abciximab
eptifibatide tirofibin |
|
MOA of abciximab, eptibatide, tirofiban (glycoprotein IIb/IIIa inbhitiors)
|
blot glcyoprotein IIb/IIIa, leads to decreased binding of fibrinogen to active platlets
|
|
Decreased binding of fibrinogen to active platelts leads to
|
decreae platelt aggregation and promoting of clot retration
|
|
What are 2 ways to treat DVT/PE
|
IV-monitored
SQ-unmonitored |
|
SEs of glycoprotein IIb/IIIa inhbitiors
|
bleeding, thrombocyotpenia
|
|
What is IV DVT/PE dose
|
Bolus: 80units/kg
Continous infusion: 18 units/kg/hr |
|
What is sub-q dose (unmonitored for DVT/PE)
|
Inital 333 units/kg
Subsequent: 250 units/kg SQ BID |
|
What is ACS and arterial thromboembolism
|
atrial fibbrilation, mechanial vavle
|
|
What is dosing for ACS and atrial fibrillation, mechanial valve
|
Bolus 60-70 units/kg
Continous infusion 12-15 units/kg/hr |
|
What is dosing for Actue MI with thrombolytic
|
Bolus: 60units/kg (max 4000)
Continous infusion: 12units/kg/hr (max 1000units/hr) |
|
What is monitoring for UFH
|
aPTT time
|
|
Why isnt there a standard aPTT time
|
different reagents, and labs and personnel
|
|
The therapeutic range is often defined as 1.5-2.5 X control values is this good measurement`
|
NO_--BAD
|
|
Each lab should establish an aPTT range than corresponds to
|
UFH plasma conc of 0.2-0.4 as measured by the protamine sulfate tiration assay
|
|
UFH plasma conc of 0.2-0.4 as measured by the protamine sulfate tiration assay or
|
0.3-0.7 as measured by anti-factor Xa assay
|
|
What case do you NOT need to monitor aPPT when giving UFH
|
for VTE prophylaxis
|
|
What reveres haprin effect
|
Protamine: 1mg : 100 units of UFH
|
|
For patients on IV infusion give 1mg protamine for every 100 units of UFH that has been given in the
|
last 3 hours-- (beyond half-life)
|