Term
1) when a small blood vessel is injured, vasospasms reduce blood flow and facilitates platelet aggregation and coagulation 2) the platelets, which adhere to extravascular collagen, are activated to release mediators that cause platelet aggregation and the formation of a platelet plug to arrest bleeding 3) exposure of the blood to tissue factors also activates coagulation and leads to the formation of a fibrin clot, which arrests bleeding until the vessel is repaired 4) after the vessel is repaired, the clot is removed by the process of fibrinolysis |
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Definition
Hemostasis occurs in what 4 steps? |
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Term
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Definition
anuclear (no cell nucleus) discoid (disc shape) contain RNA, mitochondria, lysosomes dense granules (ADP, ATP, 5HT, histamine, Ca) alpha granules (fibrinogen, Von Willebrand factor, coagulation factors V and XIII) sources of phospholipids, cofactors for coagulation factors (II, VII, IX, X) |
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Term
shape change aggregation release of alpha granule content, soluble mediators, procoagulant phospholipids (which activate thrombin and blood clotting) |
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Definition
platelet response to ADP or other aggregating agents (with cofactors fibrinogen and Ca) |
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Term
collagen - subendothelial surface thrombin - coagulation cascade |
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Definition
platelet activation involves an *increase* in *cytoplasmic Ca* platelets are stimulated by these proteins: |
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Term
ADP/ATP - from damaged cells and platelets (blocked by clopidogrel and ticlopidine) PGH2/TXA2 (thromboxane A2) - from platelets (blocked by aspirin) PAF (platelet activating factor) - from platelets 5HT - from platelets EPI/NE - circulating hormones (potentiates platelet aggregation) |
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Definition
platelet activation involves an *increase* in *cytosolic Ca* platelets are stimulated by these small molecules: |
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Term
1) TXA2 is generated from arachidonic acid in activated platelets; COX catalyzes the committed step in this process 2) secreted TXA2 binds to the cell surface TXA2 receptor, a GPCR 3) Gq activates phospholipase C 4) PLC hydrolyzes PIP2 to yeild IP3 and DAG 5) IP3 raises the cytosolic Ca concentration by promoting vesicular release of Ca into the cytosol 6) DAG activates protein kinase C 7) PKC and Ca activate phospholipase A2 8) through a poorly understood mechanism, activation of PLA2 leads to activation of GPIIb-IIIa 9) activated GPIIb-IIIa binds to fibrinogen 10) fibrinogen cross links platelets by binding to GPIIb-IIIa receptors on other platelets. This cross linking leads to platelet aggregation and formation of a primary hemostatic plug |
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Definition
platelet activation by thromboxane A2 |
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Term
PGI2 - from endothelium PGD2 - from platelets adenosine - releaed by hypoxic cells, formed during ADP/ATP degredation (facilitated by dipyridamole) NO - from platelets and endothelium |
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Definition
platelet inhibition involves an *increase* in cytoplasmic cyclic nucleotides *(cAMP or cGMP)* platelets are inhibited by: |
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Term
aspirin, dipyridamole, clopidogrel, ticlopidine, abciximab, tirofiban, eptifibatide AATTCDE |
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Definition
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Term
antiplatelet drug low doses of aspirin selectively inhibit the synthesis of TXA2 without having much effect on prostacyclin (a natural inhibitor of platelet aggregation) aspirin irreversibly inhibits COX, the enzyme that catalyzes the early step in TXA2 synthesis aspirin inhibits platelet aggregation for the life of the platelet *(5-7 days)* due to irreversible binding and effectively reduces platelet aggregation when administered once a day or every other day the platelets do not have a nucleus so they cannot make more COX enzymes. |
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Definition
mechanism of action of aspirin |
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Term
low doses of aspirin (80-160mg) have minimal adverse effects therapeutic doses of aspirin (650-975mg) can cause gastric irritation and contribute to GI bleeding and peptic ulcer excessive doses of aspirin produce toxic effects including hyperventilation, fever, dehydration, and severe metabolic acidosis aspirin hypersensitivity |
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Definition
adverse effects of aspirin |
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Term
antiplatelet drug acts primarily by inhibiting platelet aggregation *increases* intracellular concentrations of *cAMP* by inhibiting *PDE3* increases extracellular *adenosine* by inhibiting cellular reuptake, and by inhibiting adenosine breakdown adenosine binds to GPCRs (increases incracellular concentration of cAMP) reduces activation and expression of cell surface GPIIb/IIIa receptors dipyridamole is also a coronary vasodilator by increasing intracellular levels of cGMP via inhibiting PDE5 |
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Definition
mechanism of action of dipyridamole |
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Term
GI effects myalgia dizziness, headache flushing, hypotension, tachycardia hypersensitivity reactions |
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Definition
adverse effects of dipyridamole |
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Term
antiplatelet drugs these agents are prodrugs that require conversion to the active thiol metabolites
inhibit platelet aggregation by *irreversible* blockade of the *ADP* receptors on platelet membrane; *P2Y12* receptor coupled with *Gi* and *P2Y1* receptor coupled with *Gq*
[image] |
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Definition
mechanism of action of ticlopidine and clopidogrel |
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Term
[image] 1) binding of ADP to the P2Y12 receptor activates a Gi protein, which inhibits adenylyl cyclase 2) inhibition of AC decreases synthesis of cAMP, and hence decreases PKA activation. cAMP is metabolized to AMP by PDE. 3) PKA inhibits platelet activation through a series of poorly understood steps. Therefore, the decreased PKA activation that results from ADP binding to the P2Y12 receptor causes platelet activation 4) thrombin proteolytically cleaves the extracellular domain of its receptor, allowing thrombin to bind and activation Gq 5) ADP also activates Gq by binding to the P2Y1 receptor 6) Gq activation activates PLC 7) PLC activity leads to platelet activation |
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Definition
platelet activation by ADP and thrombin |
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Term
neutropenia - reduced # of neutrophils; ticlopidine thrombocytopenia - reduced # or platelets; ticlopidine thrombotic thrombocytopenic purpura (TPP) - microscopic thrombosis throughout the whole circulation. doesn't clog vessels but the RBCs can burst b/c of it. lower RBCs, anemia, kidney damage; ticlopidine less adverse effects with clopidogrel the GI effects of clopidogrel are similar to those of aspirin |
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Definition
adverse effects of ticlopidine and clopidogrel |
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Term
antiplatelet drug abciximab is a murine monoclonal antibody with the Fc fragment removed to prevent immunogenicity the FAb fragment is then joined to the human Fc region to form a chimeric molecule abciximab binds *irreversibly* to the GPIIb/IIIa receptors and blocks the binding of fibrinogen abciximab can reduce platelet aggregation by more than 90% administered via IV infusion |
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Definition
mechanism of action of abciximab |
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Term
bleeding thrombocytopenia abciximab can cause nausea, vomiting, hypotension, bradycardia, headache hypersensitivity occasionally |
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Definition
adverse effects of abciximab |
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Term
antiplatelet drugs tirofiban and eptifibatide are competitive *reversible* inhibitors of fibrinogen binding to GPIIb/IIIa receptors eptifibatide is a cyclic heptpeptide from rattlesnake venom, whereas tirofiban is a non-peptide inhibitor both of these agents have short half lives and are given as an IV loading dose followed by a maintenance infusion tirofiban and eptifibatide are primarily used in persons with acute coronary syndromes (unstable angina and MI) bleeding is a major adverse effect of tirofiban and eptifibatide administered via IV infusion |
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Definition
mechanism of action of tirofiban and eptifibatide |
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Term
[image] intrinsic pathway: contact activation pathway extrinsic pathway: tissue factor pathway; initiated at sites of vascular injury by the expression of tissue factors on several different cell types including activated endothelial cells, activated leukocytes Ca and phospholipids are a cofactor for many reactions Basically...intrinsic and extrinsic converge at X -> Xa which converts prothrombin (II) to thrombin (IIa) with Ca and PL as cofactors. thrombin activates fibrinogen to fibrin and factor XIII to XIIIa with Ca as a cofactor. fibrinogen binds to activated platelets. XIIIa stabilizes fibrin and a blood clot is formed. |
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Definition
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Term
Ca and phospholipids - enhance the activation of clotting factors; ex)VIIa, Xa viatmin K - is essential for post translational modification of factors *II, VII, IX, X* |
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Definition
cofactors for the coagulation cascade |
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Term
protein C - degrades Va and VIIIa antithrombin - a serine protease inhibitor that inhibits the activity of IIa(thrombin), VIIa, IXa, Xa, XIa, XIIa antithrombin is constitutively active and its binding to heparin increases its activity by 1000x |
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Definition
inhibitors of the coagulation cascade |
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Term
tissue factor [image] extrinsic pathway |
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Definition
exposure of plasma to ( ) initiates coagulation |
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Term
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Definition
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Term
warfarin and dicumarol are structurally related to vitamin K
these agents block the reduction of oxidized vitamin K (by inhibiting expoxide reductase) and thereby prevents the post-translational carboxylation of clotting factors *II, VII, IX, X* |
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Definition
mechanism of action of oral anticoagulants |
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Term
bleeding, which can range in severity from mild nosebleed to life-threatening hemorrhage; antidote = *phytonadione* (vitamin K) contraindicated in pregnancy b/c of their potential to cause fetal hemorrhage and various structural malformations |
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Definition
adverse effects of oral anticoagulants |
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Term
broad spectrum antibacterial agents which suppress the production of vitamin K by gut bacteria; increase anticoagulation effect of warfarin *vitamin K is enriched in kale, collards, spinach and other green leaf vegetables* NSAIDS displace warfarin from its binding site on plasma proteins; increase its effect amiodarone and cimetidine inhibit the CYP450 mediated metabolism or warfarin; increase its effect phenytoin, phenobarbital, and alcohol reduce the effect of warfarin by increases it's metabolism. |
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Definition
drug interactions of oral anticoagulants |
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Term
prothrombin time (PT) INR = (PTobserved/PTcontrol)^ISI INR = international normalized ratio ISI = international sensitivity index *for most indications, an INR or 2-3 is recommended* |
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Definition
a measure of the extrinsic (tissue factor) pathway of coagulation determine the clotting tendency of blood usage: monitor warfarin dosage liver damage vitamin K status method: 1) blood is drawn into a test tube containing liquid citrate 2) the blood is mixed, then centrifuged to separate the blood cells from plasma 3) the plasma is put through a coagulation machine 4) excess Ca and tissue factors are added, and the time the sample takes to clot is measured clotting time = 11-12 seconds |
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Term
activated partial thromboplastin time (aPTT) |
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Definition
a measure of the intrinsic pathway of coagulation uses: detect abnormalities in blood clotting, monitor the treatment effects of heparin method: 1) blood is drawn into a test tube containing liquid citrate 2) the blood is mixed, then centrifuged to separate blood cells from plasma 3) in order to activate the intrinsic pathway, phospholipid, Ca, and an activator (such as silica or kaolin) are mixed into the plasma sample 4) the time the sample takes to clot is measured. clotting time = 21-32 seconds |
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Term
heparin fondaparinux (synthetic pentasaccharide) enoxaparin, dalteparin, tinzaparin (low molecular weight heparin) bivalirudin danaparoid (a mixture of low molecular weight sulfated glycosaminoglycans: heparin sulfate, dermatan sulfate, and chondroitin sulfate) |
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Definition
parenteral anticoagulant drugs |
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Term
heparin inactivates clotting factors by potentiating the activity of an endogenous anticoagulant, *antithrombin III*
antithrombin III inhibits *II(thrombin), VIIa, IXa, Xa, XIa, XIIa
heparin and related drugs bind to the pentasaccaride binding site on ATIII.
ATIII complexes inactivate factor Xa
unfractionated heparin also inactivates thrombin, whereas low molecular weight heparin has little inactivation of thrombin and fondaparinux produces no inactivation of thrombin |
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Definition
mechanism of action of heparin and related drugs |
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Term
bleeding caused by excessive anticoagulation (heparin can be neutralized by *protamine*)
heparin can cause heparin-induced thrombocytopenia (heparin/PFIV complex: antigenic)
heparin occasionally causes hyperkalemia b/c of the suppression of aldosterone secretion |
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Definition
adverse effects of heparin and related drugs |
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Term
an additive risk of bleeding in patients receiving platelet inhibitors, thrombolytic agents, or other anticoagulants when mifepristone, RU486, is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated upon contact with heparin, protamine forms a salt, neutralizing the anticoagulation effects of both drugs |
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Definition
drug interactions of heparin and related drugs |
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Term
parenteral anticoagulant hirudin analogue hirudin is a polypeptide produced by the salivary gland of the medicinal leech hirudin and its analogues are *direct thrombin inhibitors* that do not require antithrombin III as a cofactor bivalirudin is a synthetic derivative of hirudin bivalirudin is used to prevent thrombosis in patients with unstable angina and acute MI |
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Definition
mechanism of action of bivalirudin |
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Term
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Definition
fibrinolysis: the physiological mechanism for dissolving the fibrin meshwork in a thrombus |
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Term
alteplase reteplase strepokinase |
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Definition
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Term
the fibrinolytic drugs are enzymes that convert plasminogen to plasmin plasmin degrades fibrin and fibrinogen and thereby causes clot dissolution alteplase is a recombinant plasminogen activator of the naturally occurring t-PA reteplase is a recombinant plasminogen activator containing 355 of the 527 aa of t-PA streptokinase must first combine with plasminogen to form an active complex that converts inactive plaminogen to plasmin |
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Definition
mechanism of action of fibrinolytic drugs |
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Term
the most common adverse effect is hemorrhage arrhythmias (bradycardia and tachycardia) due to free radicals generated during reperfusion streptokinase can cause hypersensitivity reaction hypotension due to the release of the vasodilator bradykinin from its circulating precursor |
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Definition
adverse effects of fibrinolytic drugs |
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Term
antifibrinolytic agent aminocaporic acid is used to treat bleeding disorders; hemophilia, patients who are recovering from GI or prostate surgery, etc. aminocaporic acid inhibits fibrinolysis by competitively blocking plasminogen activation to plasmin, and by blocking the binding of plasminogen to fibrin can be administered orally or IV adverse effects include thrombosis, hypotension, and arrhythmias |
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Definition
mechanism of action of aminocaporic acid |
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Term
antifibrinolytic agent is prescribed for excessive bleeding; hemophilia, excessive menstrual bleeding competitively inhibits the activation of plasminogen to plasmin adverse effects include nausea, vomiting, diarrhea, hypotension |
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Definition
mechanism of action of tranexamic acid |
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