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131 Cards in this Set
- Front
- Back
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Hemostasis
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cessation of blood loss from damaged a damaged vessel
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Balance of Hemostasis
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Impaired hemostasis = blood loss
Stimulated hemostasis = thrombus formation |
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4 phases of Hemostasis
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1. Vascular Spasm
2. Platelet Plug Formation (Primary Hemostasis) 3. Blood Coagulation (Secondary Hemostasis) 4. Dissolution of Fibrin Clot (Tertiary Hemostasis) |
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Vascular Spasm Flow
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Injury to Vessel Wall
Vasoconstriction: transient and locally induced by Endothelin from Endothelial Cells Slows local blood flow and increased adherence of platelets to exposed endothelial surfaces It also activates the coagulation process |
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Primary Hemostasis
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Plate Plug Formation
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Inhibitors of Platelet Aggregation released by Endothelium
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Prostacyclin
Nitric Oxide Normal so you don't get thrombosis: uninjured endothelial cells |
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What does the subendothelial consist of and why does it promote platelet aggregation/plugging?
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Basal lamina of Endothelial Cells and smooth muscle cells
Injury exposes collagen, vWF and other components of extracellular matrix |
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vWF
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Von Willebrand Factor
large multimeric protein localized in subendothelial matrix, platelet granules and in the circulation |
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What does a platelet plasma membrane contain and it's importance?
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Glycoproteins (Integrins)
bind to collagen and to vWF causes binding to subendothelium |
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What is platelet adhesion primarily mediated by?
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Integrin GPIb (glycoprotein) adheres to vWF
Integrin GPIa adheres to collagen |
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What does adhesion do toe the shape of the platelets?
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They go from flat to spherical and they extrude pseudopods to attract and interact with other platelets
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What do platelets do after adhere? (7)
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These are activated platelets and they release:
ADP Ca2+ ATP Serotonin vWF Platelet Factor 4 synthesize and release: Thromboxane A2 (TXA2) |
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ADP
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potent platelet activator via two G-protein-coupled receptors
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2 ADP receptors and their actions
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P2Y1: couples to Gq and mobilizes intracellular Ca2+
P2Y12: couples to Gi to inhibit adenylyl cyclase |
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Thromboxane A2
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platelet aggregating agonist and vasoconstrictor
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TXA2 Receptor
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Gq coupling
mobilizes intracellular Ca2+ |
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Thrombin
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enhances activation of platelets
produced from coagulation pathway |
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Thrombin Receptors
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protease-activated G protein-coupled receptors
results in activation of PLC and inhibition of adenylyl cyclase |
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What is platelet aggregation mediated by?
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Fibrinogen
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Fibrinogen
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soluble plasma glycoprotein
binds simultaneously to GPIIb/IIIa receptors on two separate platelets---> platelet crosslinking and clot formation |
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Does GPIIb/IIIa bind fibrinogen on nonstimulated platelets?
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NO
platelet activation converts GPIIb/IIIa from a low-affinity fibrinogen receptor to a high-affinity receptor |
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Secondary Hemostasis
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Blood Coagulation
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Blood Coagulation
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conversion of liquid blood into a solid gel, known as a clot.
blood coagulates by transformation of soluble fibrinogen into insoluble fibrin |
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Clot
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meshwork of fibrin within in which blood cells are trapped and functions to reinforce the platelet plug
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Thrombin
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serine protease
catalyzes the conversion of fibrinogen to fibrin: last step in the coagulation pathway |
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Hemostatic Plug
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formed after cross-linking of fibrin strands that stabilize the clot
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Coagulation Cascade
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sequence of ezymatic events
factors are usually serine proteases most factors circulate as inactive proenzymes, synthesized by the liver proenzymes are proteolytically cleaved and thereby activated, by the activated factors that procede them in the cascade intrinsic, extrinsic, and common pathways |
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Intrinsic Pathway
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activated by Factor XII (hageman factor)
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Extrinsic Pathway
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activated by Factor VII which is initiated by thromboplastin(tissue factor expressed by activated leukocytes, activated endothelial cells, sub-endothelial smooth muscle cells and subendothelial fibroblasts at the site of injury)
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Common Pathway
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both extrinsic and intrinsic pathways lead to activation of Factor X
Activated Factor X cleaves prothrombin (factor II) to thrombin (factor IIa) Thrombin converts fibrinogen to fibrin |
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Role of Vitamin K
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Factors II, VII, IX and X must undergo a vitamin K dependent post translational modification
a number of glutamic acid residues are carboxylated to gamma-carboxy-glutamic acid residues need O2, CO2, and hydroquine form or vitamin K |
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What do the gamma-carboxyglutamyl residues do?
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bind Ca2+ and are essential for interaction with platelet plasma membranes
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What is the significance of the Ca2+ chelated gamma-carboxyglutamyl residues?
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the clotting factors with the Ca2+ are able to bind to the phospholipids on the surface of platelets--->
increase in the rate at which the proteolytic activation of clotting factors can take place. |
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How is vitamin K regenerated after the reaction?
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vitamin K epoxide reductase
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Regulation of Hemostasis
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1. restricted to the local site of vascular injury
2. size of primary and secondary hemostatic plugs must be restricted |
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5 mechanisms that limit the initiation and propagation of the hemostatic process to the immediate vicinity of the injury
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1. Prostacyclin (PGI2)
2. Antithrombin III 3. Protein C and S 4. Tissue Factor Pathway Inhibitor (TFPI) 5. Tissue Type Plasminogen Activator (t-PA) |
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PGI2
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Prostacyclin
eicosanoid secreted by the endothelium increases cAMP levels within platelets and thereby inhibits platelet activation Also a vasodilator by increasing cAMP within smooth muscle |
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Antithrombin III
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iactivates thrombin and other coagulation factors (IXa, Xa, XIa and XIIa) by forming a complex with the coagulation factor
activated by heparin like molecules on the endothelial cells |
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Protein C and protein S cofactor
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vitamin K-dependent serine protease activated by thrombin
activated form degrades factors Va and VIIIa |
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Protein C and S Feedback Mechanism and mode of action.
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excess thrombin generation leads to activation of Protein C
activation is modulated via thrombomodulin (endothelial receptor for protein C and thrombin) when thrombin and protein C bind together, protein C is activated to protein Ca protein Ca +cofactor protein S then inhibits clotting by cleaving Factors Va and VIIIa inactivating them |
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Tissue Factor Pathway Inhibitor
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TFPI
limits the action of Tissue factor thus limiting TF mediated activation of Factors IX and X |
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Plasmin
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proteolytically cleaves fibrin into fibrin degredation products (fibrinolysis)
generated by cleavage of plasminogen |
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Plasminogen
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plasma protein that is synthesized in the liver
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Tissue Plasminogen Activator
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t-PA
catalyzes cleavage of plasminogen to plasmin synthesized and secreted by the endothelium |
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Thrombosis
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pathologic extension of hemostasis
uncontrolable hemostasis that increases a clots size and occludes the lumen of a blood vessel |
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Pathologic Clot
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thrombosus
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Three factors that predispose thrombus formation
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1. endothelial injury
2. abnormal blood flow 3. hypercoagulability |
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Venous Thrombosis
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triggered by blood stasis or inappropriate coagulation cascade
rich in fibrin with fewer platelets than arterial clots |
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Artherial Thrombosis
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medium sized vessels due to lesions of endothelial cells caused by atherosclerosis
consists of platelet rich clot |
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Drugs Used to Reduce Clotting
(3 categories) |
1.platelet aggregation inhibitors
2.anticoagulants 3.thrombolytics |
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Drugs Used to Treat Bleeding
(5 categories) |
1. Plasminogen activation inhibitors
2. Protamine Sulfate 3. Aprotinin 4. Vitamin K 5. Plasma Fractions |
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Platelet Aggregation Inhibitors
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decrease formation or action of chemical signals that promote platelet aggregation
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Platelet Aggregation Inhibitors Use (4)
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1.prevention and treatment of occlusive cardiovascular diseases
2.maintenance of vascular grafts 3.maintenance of arterial patency 4.adjuncts to thrombolytic therapy in MI |
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Cyclooxygenase Inhibitors
(Aspirin) |
inhibits TXA2 synthesis by irreversible acetylation of the enzyme COX
anuclear platelet can't synthesize new proteins so it can't manufacture new enzyme during it's 10 day lifetime other NSAIDs have shorter durations of action because they can't acetylate COX (actions are reversible) USE: prophylactic treatment of transient cerebral ischemia, reduce incidence of recurrent myocardial infarction, and to decrease mortality in postmyocardial infarction patients |
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ADP Receptor Blockers
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CLOPIDOGREL
TICLOPIDINE |
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ADP Receptor Blockers Action
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irreversibly inhibit P2Y12 (platelet ADP receptor)
reduce platelet aggregations |
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Clopidogrel and Ticlopidine
PK, PD, USE and AE |
prodrugs that must be metabolized to become active: not used for emergencies
prevent cerebrovascular, cardiovascular, and peripheral vascular disease irreversible platelet inhibitors that can increase the the risk of bleeding 5-7 days after stopping treatment: NO ANTIDOTE Neutropenia and Thrombocytopenic Purpura are AE Inhibit Cytochrome P450 |
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What is standard practice to prevent thrombosis in patients undergoing placement of a coronary stent?
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Usage of Clopidogrel and Ticlopidine
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Which is better Clopidegrel or Ticlopidine and why?
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Clopidogrel
fewer side effects and is rarely associated with neutropenia. and because of dosing requirements |
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Phosphodiesterase Inhibitors
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DIPYRIDAMOLE
CILOSTAZOL |
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Dipyridamole
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coronary vasodilator
prophylactically treat angina pectoris increases cAMP levels by inhibiting phosphodiesterase and/or by blocking uptake of adenosine which acts at A2 receptors to activate platelet adenylyl cyclase by itself has no beneficial effect |
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What do you take with Dipyridamole to have an effect?
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Warfarin
to prevent of postoperative thromboembolic complications of cardiac valve replacement |
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What is Aspirin + Extended release Dypyrimadole used for?
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secondary prohylaxis of cerebrovascular disease
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Cilostazol
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phosphodiesterase inhibitor
promotes vasodilation and inhibition of platelet aggregation used to treat INTERMITTENT CLUADICATION |
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Blockers of Platelet GP IIb/IIIa Receptors (3)
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ABCIXIMAB
EPTIFIBATIDE TIROFIBAN all given parenterally |
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GPIIb/IIIa blockers General
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antiplatelet agents: use in acute coronary syndromes
blocks the receptors that bind fibrinogen, vitronectin, fibronectin and vWF |
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Glanzmann's Thrombasthenia
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persons lacking the GPIIb/IIIa receptor
causes a bleeding disorder. |
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Abciximab
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chimeric mouse-human monoclonal antibody directed against the GPIIb/IIIa receptor
essentially irreversible: dissocation half time of 18 to 24 hours |
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Eptifibatide
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cyclic peptide reversible antagonist of GPIIb/IIIa receptor
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Tirofiban
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nonpeptide tyrosine analogue
reversible antagonist of GPIIa/GPIIIa receptor |
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Anticoagulants (categories based on MOA) (4)
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1.Unfractioned Heparin (UFH) and Low Molecular Weight Heparins (LMWH)
2. Selective Factor Xa inhibitors 3. Direct Thrombin Inhibitors (DTIs) 4. Coumarin Anticoagulants |
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Heparin
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injectable
rapidly acting anticoagulant used acutely to interfere with formation of thrombi anticoagulant effect is a consequence of binding antithrombin III in the presence of heparin the antithrombin actions are fast (1000 fold increase), in the absence they are slow cofactor for antithrombin-protease reaction not consumed in reaction |
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Antithrombin III
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alpha globulin that inhibits clotting factor proteases, especially thrombin, IXa and Xa by forming equimolar stable complexes with them.
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What is required in Heparin to bind antithrombin III?
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critical sequence of 5 carbohydrate residues
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Unfractionated Heparin (UFH)
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mixture of straight-chain anionic glycosaminoglycans with a molecular weight range of 5,000 to 30,0000
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Low Molecular Weight Heparin (LMWH)
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heterogenous compounds produced by chemical or enzymatic depolymerization of UFH
inhibit activated factor X but have less efect on thrombin than UFH effective in thromboembolic conditions equal in efficacy to UFH increased bioavailability from subcutaneous site of injection less frequent dosing requirements (2x) |
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LMWH drug names
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ENOXAPARIN
DALTEPARIN TINZAPARIN |
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Monitoring of Heparin Therapy
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needed to make sure that anticoagulant effect is within therapeutic levels and there is not excessive bleeding
monitor aPTT (thromboplastin time) assay |
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Thromboplastin Time (aPTT) Assay
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test of the integrity of the intrinsic and common pathways of coagulation
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Why is it generally not necessary to monitor blood activity levels of LMW heparins?
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because they have a higher therapeutic index than UFH
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LMW Heparins excretion?
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kidney: care should be taken to avoid excessive anticoagulation in patients with renal insufficiency.
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LMWH and UFH uses
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prevention of venous thrombosis
treatment of a variety of thrombotic diseases: pulmonary embolism and acute MI |
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LMWH and UFH AE
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1.Bleeding
2.Hypersensitivity 3.Thrombosis: reduction of antithrombin thus decreasing inactivation of coagulation factors and increasing risk of thrombosis 4. Heparin Induced Thrombocytopenia (HIT) |
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HIT
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Heparin Induced Thrombocytopenia
2 types: Type I: common and involves a mild decrease in platelet number due to nonimmunologic mechanisms (first 5 days of treatment) Type II: systemic hypercoagulable state that occurs in 1-4% of individuals treated with UFH for 7 days or more---> antibodies that recognize complexes of heparin and platelet protein PF4 |
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Mechanism of Type II HIT
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IgG binds to Fc receptor on platelets---> degranulation and aggregation-----> release more PF4---->platelet consumption-----> thrombocytopenia and thrombosis
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Treatment of HIT
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treated by discontinuing of heparin and administration of direct thrombin inhibitor or fondaparinux.
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Reversal of Heparin Action
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discontinuance of the drug
if bleeding occurs administer specific antagonist: protamine sulfate |
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Does protamine reverse the effect of fondaparinux?
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NO
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DANAPAROID
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LMWH derived from porcine gut mucosa
contains heparan sulfate, dermatan sulfate, and chondroitan sulfate is devoid of Heparin or heparin fragments antithrombic effect through antithrombin III-mediated inhibition of factor Xa and to a lesser extent thrombin approved for prohylaxis of DVT in hip replacement surger effective in treatment of HIT |
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Selective Factor Xa Inhibitors
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FONDAPARINUX
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Fondaparinux
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sythetic pentasaccharide that contains sequence of 5 carbohydrates needed to bind antithrombin III and induce conformational change in antithrombin required for it's binding of Factor Xa
negligible antithrombin activity |
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Fondaparinux
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approved for prevention and treatment of DVT
once daily SC injection |
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Direct Thrombin Inhibitors (DTIs)
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exert anitcoagulant effect by directly binding to active site of thrombin
LEPIRUDIN DESIRUDIN BIVALIRUDIN ARGATROBAN |
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Lepirudin
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recombinant form of Hirudin from the leech
thrombin inhibitor can reach and inactivate both free and fibrin-bound thrombin in developing clots paraneterally and monitered via aPTT Approved for thrombosis related HIT excreted by kidney NO ANTIDOTE EXISTS |
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Desirudin
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another recombinant form of huridin
prophylaxis against DVT in patients undergoing hip replacement aPTT monitoring |
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Divalirudin
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bivalent inhibitor of thrombin
IV also inhibits platelet activation monitored aPTT Use in percutaneous coronary angioplasty |
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Argatroban
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small molecule thrombin inhibitor
use for HIT with or without thrombosis and coronary angioplasty in patients with HIT IV monitor aPTT |
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Coumarin Anticoagulants
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WARFARIN
DICUMAROL oral anticoagulants antagonize function of vitamin K |
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Coumarin MOA
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inhibit vitamin K epoxide reductase therefore vitamin K is unable to be reused in the vitamin K depenendent post translational modification for factors II, VII, IX, X
produces inactive clotting factors effects are not observed until 8-12 hours after admin. can be overcome by administering vitamin K, but takes about 24 hrs |
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Monitoring of Warfarin Levels
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Narrow therapeutic index
many drug-drug interactions monitor every 2-4 weeks monitor via PT |
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PT
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prothrombin time
test of the integrity of the extrinsic and common pathways of coagulation plasma is added to crude preparation of tissue factor (thromboplastin) and time for formation of fibrin clot is measured measurement is expressed as International Normalized Ratio of prothrombin time to that in a control sample |
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Which vitamin K dependent factor has the shortest half life?
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Factor VII
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Warfarin AE
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1. hemorrhage: may need to give whole blood, plasma concentrates or frozen plasma (with factors), vitamin K and withdraw drug
2. Cutaneous Necrosis: due to reduce activity of protein C: pathological lesion associated with with hemorrhagic infarction is venouse thrombosis 3. Crosses Placenta readily and can cause hemorrhagic disorder in the fetus |
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Drugs that INHIBIT Warfarin Metabolism
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Cimetidine
Chloramphenicol Disulfiram Fluconazole Metronidazole Phenylbutazone Sulfinpyrazone Trimethoprim-Sulfamethoxazole |
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Drugs that STIMULATE Warfarin metabolism
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Barbituates
Carbamazepine Phenytoin Rifampin |
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Thrombolytic (Fibrinolytic) Drugs
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used to lyse already formed clots
act by converting the inactive zymogen plasminogen to active protease plasmin that digests fibrin also dissolves physiologically appropriate clots and therefore cause hemorrhage |
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What are Thrombolytic Agents Contraindicated with?
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1. Healing wounds
2. Pregnancy 3. History of Cerebrovascular Accident 4. History of Metastatic Cancer |
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Thrombolytic Drugs Uses
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1.used now for unclotting catheters and shunts by lysing clots causing occlusion
2.also used to dissolve clots that result in strokes. 3.reduce mortality of acute MI and are used in situations in which PCI (angioplasty) is not readily available |
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Thrombolytic Drug Names
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STREPTOKINASE
UROKINASE ALTEPLASE, RETEPLASE, TENECTEPLASE ANISTREPLASE |
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Streptokinase
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protein produced by B-hemolytic streptococci
combines with plasminogen and converts plasminogen to plasmin also catalyzes degredation of fibrinogen and clotting factors V and VII Used in acute MI, acute pulmonary embolism, arterial thrombosis, and occluded shunts rarely used clinically |
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Urokinase
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human enzyme synthesized by kidney and found in urine
converts plasminogen to plasmin used in lysis of pulmonary emboli |
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Alteplase, Reteplase and Tenecteplase
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recombinant Tissue plasminogen activator
selective to plasminogen bound to fibrin high concentrations of t-Pa can lead to hemorrhage. |
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Alteplase
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biological half-life 3-6 min
approved for treatment of acute MI, acute massive pulmonary embolism and acute ischemic stroke |
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Reteplase
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modified recombinant t-Pa
less fibrin specific that t-Pa half life is 14-18 min can be given as a double bolus (two boluses, 30 minutes apart) used in management of acute MI |
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Tenecteplase
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mutant form of t-Pa
half life of 20-24 min. given as single IV bolus more fibrin specific than t-Pa used in reduction of mortality associated with MI |
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Anistreplase
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complex of purified plasminogen and bacterial streptokinase that has been acylated to protect the enzyme's active site
when admin. the acyl group hydrolysis freeing activator complex discontinued in US |
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What is the major toxicity of thrombolytic agents and what 2 factors does it result from?
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Hemorrhage
1. lysis of fibrin in "physiological thrombi " at sites of vascular injury 2. Systemic Lytic state from systemic formation of plasmin |
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Venous Thrombosis Prevention
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SC admin of low dose Unfractioned heparin, LMW heparin or fondaparinux
Warfarin is alos effective but requires monitoring |
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Venous Thrombosis Treatment
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initiated with UFH or LMWH for 5-7 days with an overlap of warfarin
warfarin is continued for 3-6 months |
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What is venous thromboembolic disease in pregnant women treated with
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heparin given SC
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Artherial Thrombosis Clinical
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1. Aspirin and Clopidogrel or Ticlopidine is indicated in patients with Transient ischemic attacks and strokes or unstable angina
2. In angina and MI the above drugs are used in combination with B-blockers, calcium channel blockers and fibrinolytic drugs |
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Antiplatelet and Anticoagulant Drugs of Choice
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Go over Table Pg. 15
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Plasminogen Activation Inhibitors
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AMINOCAPROIC ACID
TRANEXAMIC ACID |
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Aminocaproic Acid and Tranexamic Acid
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synthetic agents that inhibit plasminogen activation
Uses: 1. adjunctive therapy in hemophilia 2. therapy for bleeding from fibrinlyitic therapy 3. Prophylaxis for rebleeding from intracranial aneurysms 4. Postsurgical GI bleeding 5. Postprostatectomy bleeding 6. Bladder hemorrhage secondary to radiation and drug induced cystitis |
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Aminocaproic Acid and Tranexamic AE
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1. intravascular thrombosis
2. hypotension 3. myopathy 4. adbominal discomfort 5. diarrhea 6. nasal stuffiness C.I. in DIC, genitourinary bleeding or upper tract (kidney and ureters) due to excessive clotting |
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Protamine Sulfate
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chemical antagonist of heparin
derived from fish sperm testes: high in arginine positively charged and acts with negatively charged heparin to form stable complex---> no anticoagulant activity does not work against Fondaparinux given IV to reverse effects of heparin in life threatening situations |
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Protamine Sulfate AE
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can interfere with coagulation when given in absence of heparin since the basic protein can interact with platelets and fibrinogen
hypersensitivity dyspnea flushing bradycardia hypotension |
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Vitamin K
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can stop bleeding problems due to oral anticoagulants
effect is delayed for 6 hours but is complete by 24 hrs |
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Serine Protease Inhibitors
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APROTININ
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Aprotinin
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stops bleeding by blocking plasmin.
also inhibits plasmin-streptokinase complex approved for use in patients undergoing coronary artery bypass surgery who are at risk of excessive blood loss withdrawn 2007 because it increased risk of death |
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Plasma Fractions Uses
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Factor VIII defciency (Hemophilia, or Hemophilia A)
Factor IX deficiency (christmas disease or Hemophilia B) |
