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213 Cards in this Set
- Front
- Back
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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
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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
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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
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thrombosis at early age
VTE w/ family history reccunet VTE, or unexplained spontaneous aborption |
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Most common Acquired hyper-coaguable disorder
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Antiphospholipid antibody syndrome
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What are causes of Antiphospholipid antibody syndrome
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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
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vitamin K depends, C inactaion factor V and VIII
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Elevated levels of homcytemisemia are know to be raks for for
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aterial and venous thrombosis
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Antithrombin Deficiency normally
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inctive thrombin and other serine protease
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What does Prothiombin Gene mutation G 20210A do
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increae prothrombin activity and levels--increase risk for clot
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Vita K is necessary for syntheisis of activated clotting factors, and
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,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
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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
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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
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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
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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
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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
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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
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LMWH
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Major SE's considerations with Heparin and LMWH
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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
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from bovine lung than porvine intestine
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Thrombocytopenia involves heparin binding to
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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
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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
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bind to heparin and inactivates
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Protamine is less effective against
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LMWH
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Protamine should be infused slowly b/c
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high doses ALSO exert anti-coagulation activity making matter worse
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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
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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
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sub-q
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No monitoring aPPT with fonadparinux--but be careful with
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increased risk of bleeding and renal clearance
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What are ATIII-INDEPEDNET thormbin ihbitiors (inhibit thrombin withOUT ATIII
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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
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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
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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
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recombinant form of activated anticoagulaant C
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What does drotecogin alfa do
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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
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warfarin, anisindione
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What is MOA of warfarin
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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
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vit K is trap in the oxidzied form
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Vitamin K is only active in the
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reduced hydroxylated or hydroquione form
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In essense warfarin decrease formation of active vit K, leading to
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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
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wafarin becue oral activyt and long half life (40)
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How is warfarin monitored
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INR (international normalized ratio)
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What are warfarins major PK interactions
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99% bound to albumun
meatbolized by hepatic microsomal enzymes vitamin K availability |
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Is wafarin contraindicated in pregnacy
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YES
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The anticoagulation effects of warfarin can be reversed by
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discontinuation
or by vitamin K +- factor 9, or fresh-frozen plasma |
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B/c wafarin is 99% protein bound it can be displaced leading to
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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 |
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How do antibiotics affects vitamin K avaialbility
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GI bacterai synthezie vitK--antibiotic kill vitamin K---leading to increased anticoagluation
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How do leafy green veggies affect Vitamin K
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decreases anticoagulation
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Inhibition Vitamin K--inhibits factors 2,7,9,10 and
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anticoagulant C and S
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What is signifgant about wafarin ihhibiting ANTI-coagulant C and S
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may see prothrombotic effect during 1st few days of therapy
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Why is a prothormbic effect seen 1st few days of therapy
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due to short half-life of anti-coagulatnt C
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How is temporary prothrombotic activity of wafarin overcome
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1st few days use heparin with warfarin
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Warfarin may also cause a purple toe syndrome--located and when develop
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painful, blue-tinged toes, and plantar surface that may develop 3-8 weeks into therapy
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What are examples of ATIII indepdent Xa inhibtiors
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apixaban, and rivaroxaban
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Apixaban and rivaroxaban MOA
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selective ihbitiors of Xa--inhibiton of coagulation
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What is the therapeutic objective of thrombolytic agents
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prmotes clot break down through fibrinolysis--restablish blood flow
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When must thrombolytic therapy be instituted
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soon after occurrence of symptoms--b/c fibrin b/c more corss linked and it is harder to degrade
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Can occulsion of cornary atery can cause
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MI or ischemia
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What was 1st thrombolytic agents
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streptokinase
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What is stretokinase extracted from
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hemolytic steptococci
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MOA of stretokinase
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forms a stable 1:1 complex with plasminogen--causing a conformational change to form plasmin--plasmin degrades fibirin
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SEs of Streopkinase
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blleeding-
allergic reactions--due to antigenticty neutralizing antibodies |
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What are neutralizing antibodies with streptokinase
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pts who had a prior steptococcal infection, may make antibodies againsts strep--rendering the drug ineffecitve
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What is MOA of anistreplase
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acts by binding to fibrin and undergoing deacylation
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Anistreplase binds to fibrin and undergoes deacylation (SLOW)--conversion fo plasminogen to plasmin---and leads to
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clot lysis
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What makes anisreplase WAY BETTER than stretokinase
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more clot selective b/c binds to fibrin
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What is MOA of urokinase
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acts by binding plasminogen and converting to plasmin--and degregation of clot
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How is urokinase administered
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iv--
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SEs of urokinase
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bleeding, liitle or no fibrin speciificty and alpha antiplasmin depletion
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What is the most selective thrombolytic agent
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Tissue plasminogen activator (TPA)
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MOA of TPA
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binding fibrin AND plasminogen to form a trimolecular comples, formins plasmin, have clot degration
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How is TPA administered
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IV
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What are NEWER plasminogen activator
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lanoteplase
tenecteplase reteplase |
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Which plasminogen activator has shorter half-life than tpa
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reteplase
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Benefits of lanoteplase and teneteplase
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longer duration of action--no need to infuse continously like tpa, single injection ok
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What are therapeutic uses of plasminogen/plasmin inbhitiors
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prevent excessive fibrinolysis
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What is an Plasminogen/plasmin inhibitition
|
aminocaporic acid
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MOA of aminocaprioic acid
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binds to plasminogen and plasmin via lysine binding BLOCKING plamsin binding to fibirin
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Aminocaprioic acids has been used in
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tooth extraction and after prostate surgery in hemophiliacs
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What are antiplatelt agents
|
Aspirin
Purinergic receptor antagoinsts Glycoprotein IIb/IIIa inhibtiors |
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Aspirin MOA
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irrversible inhibitor of COX leading to decrease formation of Thromboxane A2, and decrease pletlat aggreation
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What are purinergic receptor anatagonists
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ticlopidine, clopidogrel
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Ticlopidine, and clopidergrela are pro-drugs which are converted to
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active metabolites
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MOA of Purinergic receptor antagoinsts
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ADP receptor antagoinsts--preventing ADP platelt aggretion
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Ticlopdinea nd clopidogren have slot onset of actions, thus
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loading dose may be needed
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Major side effects of ticlopdine, why its generally not use
|
neutropenia, and thrombocytopenia puppra TTP
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What are Glycoprotein IIb/IIIa inhibitors
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abciximab
eptifibatide tirofibin |
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MOA of abciximab, eptibatide, tirofiban (glycoprotein IIb/IIIa inbhitiors)
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blot glcyoprotein IIb/IIIa, leads to decreased binding of fibrinogen to active platlets
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Decreased binding of fibrinogen to active platelts leads to
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decreae platelt aggregation and promoting of clot retration
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What are 2 ways to treat DVT/PE
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IV-monitored
SQ-unmonitored |
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SEs of glycoprotein IIb/IIIa inhbitiors
|
bleeding, thrombocyotpenia
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What is IV DVT/PE dose
|
Bolus: 80units/kg
Continous infusion: 18 units/kg/hr |
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What is sub-q dose (unmonitored for DVT/PE)
|
Inital 333 units/kg
Subsequent: 250 units/kg SQ BID |
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What is ACS and arterial thromboembolism
|
atrial fibbrilation, mechanial vavle
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What is dosing for ACS and atrial fibrillation, mechanial valve
|
Bolus 60-70 units/kg
Continous infusion 12-15 units/kg/hr |
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What is dosing for Actue MI with thrombolytic
|
Bolus: 60units/kg (max 4000)
Continous infusion: 12units/kg/hr (max 1000units/hr) |
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What is monitoring for UFH
|
aPTT time
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Why isnt there a standard aPTT time
|
different reagents, and labs and personnel
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The therapeutic range is often defined as 1.5-2.5 X control values is this good measurement`
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NO_--BAD
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Each lab should establish an aPTT range than corresponds to
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UFH plasma conc of 0.2-0.4 as measured by the protamine sulfate tiration assay
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UFH plasma conc of 0.2-0.4 as measured by the protamine sulfate tiration assay or
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0.3-0.7 as measured by anti-factor Xa assay
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What case do you NOT need to monitor aPPT when giving UFH
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for VTE prophylaxis
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What reveres haprin effect
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Protamine: 1mg : 100 units of UFH
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For patients on IV infusion give 1mg protamine for every 100 units of UFH that has been given in the
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last 3 hours-- (beyond half-life)
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