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53 Cards in this Set
- Front
- Back
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blood coagulation
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-activation of X to Xa
-conversion of II (prothrombin) to IIa (thrombin) -thrombin-mediated transformation of fibrinogen to fibrin (involves activation of XIII) |
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other effects of thrombin
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-promotes platelet aggregation
-convert V and VIII to active forms -intitiates antioagulant protein C pathway |
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protein C pathway
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-thrombin cleaves pro C --> APC
-APC cleaves Va and VIIIa to giveinactive products -accel in presence of protein S (both C and S are vit-K dependent) |
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Factor V Leidin
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-mutation-- greatest risk factor for thrombolysis
-single bp substitution at site on V that is cleaved by APC--> APC-resistant --> reduced anticoagulant response |
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heparin physical properties
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-mixture of sulfated polysaccharides
-highly neg charged -commercially from porcine intestine |
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heparin mech
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-inc rate of thrombin-antithrombin rxn x1000
-induces conformational change in antithrombin so it is more accessible by coagulation factor -antithrombin inhibits activated coag factors (thrombin, Xa, IXa) -does NOT affect synthesis of clotting factors |
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heparin absorption and metabolism
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-size and polarity prevent gut absorption --> IV or subcut
-does NOT cross placenta-- used in pregnancy -cleared by reticuloendothelial system and liver |
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monitoring heparin
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-aPTT: 1.5-2.5 times normal (50-80 sec) indicates therapeutic
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heparin sues
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-dec risk of DVT recurrence
-cardiopulmonary bypass -prophylactic to prevent DVT (low dose, no effec ton aPTT) |
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heparin s/e
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-bleeding (1-5%) -- can be controlled with protamine sulfate
-heparin-induced thrombocytopenia |
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heparin-induced thrombocytopenia
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-IgG ab's developed against heparin bound to platelet factor 4
-the IgG-heparin-PF4 complex binds FcgIIa receptor on platelets --> platelet activation --> aggregation --> thrombocytopenia |
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heparin uses
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-emergency/initial treatment of DVT or PE
-initial management of unstable angina or acute MI -low dose to prevent DVT and thromboembolism -hemodialysis, blood samples, maintain patency of arterial catheters -anticoag during pregnancy |
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low molecular weight heparin mech
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-enoxaparin & dalteparin
-binds to and accel activity of antithrombin III --> inhibits Xa (blocks prothrombin to thrombin) -longer t1/2 than heparin, subcut administration |
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LMW heparin uses
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-enoxaparin and dalteparin
-treat acute DVT -prophylax DVT -acute unstable angina and MI -hip replacement surgery |
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lepirudin mech
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-from leech
-specific thrombin inhibitor that inactivates thrombin by blocking substrate binding -IV |
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lepirudin use
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-pts that have previously presented with heparin-induced thrombocytopenia
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protamine sulfate
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-heparin antagonist
-positively charged molecule -can cause anaphylaxis with bradycardia, vasodil, hypoTN -can cause severe pulm HTN -used to reverse heparin following cardiopulmonary bypass |
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warfarin mech
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-vit K antagonist
-blocks VKORC1 to prevent KO--> KH2 (reduced form) -no KH2 available for y-carboxylation of f II,VII, IX, X |
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monitoring warfarin
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-use INR
-ratio of patient PT to a control PT -normal: .8-1.2 -warfarin working: 2-3 |
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warfarin absorption and metab
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-rapidly absorbed after oral administration
-extensively bound to plasma albumin (>99%) -converted to inactive metabolites by liver (mainly CYP2C9) |
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warfain s/e
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-hemorrhage
-c/i like heparin -crosses the placenta and is tetartogenic -prolonged action in liver or kidney disease or vit K deficiency -narrow ther window |
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reversal of warfarin
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-administration of vit K (but may take days to make new active coag factors)
-immediate reversal requires exogenous administration of active clotting factors |
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warfarin use
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-long-term treatment of venous thromboembolic disease
-prophylax against thromboembolism in atrial fib -prophylax against thromboembolism in pts with prosthetic heart valves -prophylax against thromboembolism in pts with DCM |
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warfarin genetics
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-CYP2C( *2 and *3): enzyme with decreased activity, higher drug concentrations means need a lower dose
-VKORC1: A clade= low expression of VKORC1= requires lower dose |
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dabigatran mech
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-prodrug
-specific, reversible direct thrombin inhibitor (both free and firbin-bound thrombin) -prevents cleavage of fibrinogen, activation of V, VIII, XI, XIII -inhibits thrombin-induced platelet aggregation |
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dabigatran metab
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-hydrolyzed to active form by plasma and hepatic esterases
-hepatic glucuronidation via Pgp's |
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dabigatran drug interactions
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-Pgp inducers dec plasma concentration
-Pgp inhibitors inc plasma conc |
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dabigatran uses
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-post-op thromboporphylaxis for knee/hip replacement
-prevention of stroke and systemic embolism in pts with nonvalvular a-fib |
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rivaroxaban mech
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-reversible binding with Xa
-inhibits both free and thrombus-assoc f Xa -metab via CYP3A4, 3A5, P2J2 |
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rivaroxaban drug interactions
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-Pgp/CYP3A4 inhibitors: inc plasma conc
-Pgp/CYP3A4 inducers: dec plasma conc |
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rivaroxaban uses
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-dec risk of stroke/systemic embolism in pts with nonvalvular a-fib
-prophylaxis of DVT in pts undergoing knee/hip replacement |
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fibrinolytic system
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-dissolves intravascular clots
-plasminogen --> single peptide bond cleaved --> plasmin -Nterm: 5 disulfide loops (kringles)= lysine binding sites that bind lysine residues in polymerized fibrin -Cterm: active catalytic site |
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endogenous activators of plasminogen to plasmin
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-tPA: binds fibrin; activates fibrin-bound plasminogen
-plasma purokinase: converted to urokinase by kallikrein; enhances fibrin-bound plasminogen activator |
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altepase
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-tPA
-poor enzyme in absence of fibrin -specifically activates fibrin-bound plasminogen -rapid hepatic clearance--> constant IV |
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complications of thrombolytic therapy
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-hemorrhage
-systemic lytic state (fibrogenolysis and destroys clotting factors) -bleeding occurs even with specificity of altepase -proportional to dose and duration |
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indications for thrombolytic therapy
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-manage ST-elevation MI for lysis of thrombi in coronary arteries
-manage acute ischemic stroke -manage acute pulm embolism |
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c/i to thrombolytic therapy
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-active bleeding
-recent surgery -GI bleeding within 3 months -recent CVA -hemorrhagic disorder or hypersensitivity -uncontrolled HTN -pregnancy or postpartum |
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procoagulant drugs
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-amincaproic acid
-synthetic lysine analog --> blocks binding of plasmin to fibrin -dec hemorrhage with surgical procedures -useful to treat urinary tract bleeding |
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platelet membrane proteins (integrins)
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-GPIa and GPIb
-bind to collagen and vWF -cause platelets to adhere to the subendothelium of a damaged blood vessel |
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PAR1/PAR4
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-protease-activated receptors on platelets
-respond to thrombin (IIa) -activate GPIIb/GPIIIa (fibrinogen-binding) -activate cox1 -promote platelet aggregation and secretion |
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P2Y1/P2Y12
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-purinergic receptors for ADP
-activate GPIIb/GPIIIa (fibrinogen-binding) -activate cox1 -promote platelet aggregation and secretion |
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fibrinogen binding to platelets
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-results in cross-linking of adjacent platelets
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aspiring and platelets
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-inhibits platelet cox 1 and 2
-works for the lifetime of the platelet -blocks TXA2 formation |
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dipyridamole mech
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-phosphodiesterase inhibitor --> inc cAMP --> inhibits platelet aggregation
-blocks uptake of adenosine |
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dipyridamole uses
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-prevents thromboemboli (with warfarin) in pts with prosthetic heart valves
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ticlopidine/clopidogrel mech
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-binds P2Y1/12 receptors --> blocks effects of ADP
-normally, ADP couples to Gi and dec cAMP --> platelet aggregation -prolongs bleeding time, inhibits platelet agg, delays clot retraction |
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ticlopromide/clopidogrel metabolism
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-need to be metabolized to active form by CYP2C19
-poor metabolizers have lower active drug concentrations |
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ticlopidine s/e
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-blood dyscrasias
-neutropenia |
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ticlopidine uses
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-2* prevention of CV disease
-MI -unstable angina -coronary artery stenting -periph vascular disease -pts with transient ischemic attacks -strokes |
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clopidogrel uses
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-MI prophylaxis
-stroke prophylaxis |
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abciximab mech
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-binds GPIIb/IIIa --> prevents binding of fibrinogen/vWF/other adhesive molecules --> inhibits platelet agg
-IV bolus injection followed by continuous infusion |
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abciximab s/e
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-bleeding
-thrombocytopenia |
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abciximab uses
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-adjunct to percutaneous coronary intervention for preventing ischemic complications
-intended for use with aspirin and heparin only |
