11/5 Flashcards
slow PT
(prolonged time)
defect in extrinsic or common coagulation pathways
-warfarin therapy
slow aPTT
(prolonged time)
defect in intrinsic or common coagulation pathways
-heparin therapy
therapeutic INR
2-3
Oral anticoagulant examples
coumarin
indandione - not used clinically
coumadin MOA
inhibits vitamin K-epoxide reductase - blocking reduction of vit K epoxide back to its active form
vit K is needed to form prothrombin
warfarin therapeutic actions
delayed onset - must deplete pool of circulating clotting factors, maximal effect is not observed until 3-5 days after initiation of therapy
after discontinuing therapy: factors must be resynthesized to return to normal PT
warfarin metabolism
metabolized by CYP2C9 - lots of variability
t1/2 = 36-48 hours
warfarin termination of action
is not correlated with plasma drug levels, but reestablishment of normal clotting factors
warfarin overdose
latrogenic hemmorrhage
- discontinue warfarin therapy
- administer Vit K1 - can activate warfarin-inhibited reductase
- in serious hemorrhage - plasma replaces clotting factors faster tan Vit K therapy
warfarin adverse effects
latrogenic hemorrhage
-risk of bleeding increases with intensity and duration of therapy
use during pregnancy
-CI in women who are or may become pregnany
-passes freely through placenta
-spontaneous abortions
-fetal hemorrhage
-birst defect: nasal hypoplasia and abnormal bone formation
drug interactions with warfarin - increased prothrombin time
PK - amiodarone, cimetidine, disulfiram, metronidazole, fluconazole, gemfibrozil, sulfinpyrazone
PD - aspirin, cephalosporins
drug interaction with warfarin - decreased prothrombin time
PK - barbituates, cholestryamine, rifampin
PD - diuretics, vit K
parenteral anticoagulants
- heparin (unfractionated heparin - UFH)
- LMWH
- non-heparinoids
heparin MOA
- binds to positively charged to antithrombin III (AT)
- increases the rate at which AT interacts with plasma proteases clotting factors (1000 fold increase)
- dissociates and can interact with more AT
AT can inactivate throbmin and factors Xa, VIIa and IXa
heparin administration
intermittent IV, continuous IV, SC
heparin clinical use
- adjust dosing according to coag tests - aPPT therapeutic range = 1.5-2 x normal
- t1/2 30-180 min
- anticoag effect dissappears within hours of discontinuation of therapy
heparin hemorrahge
- iatrogenic hemorrhage
- can occur at any site
- risk factors: over 50, ulcer patients, severe HTN, antiplatelet drugs
- treatment: stop heparin, adm specific antagonist if life-threatening (protamine sulfate)
heparin other AEs
- thrombocytopenia:
- mild, transiet (25%) due to direct action on platelets
- severe (5%) develops 7-12 days after starting therapy antibodies develop to platelet (PF4)-heparin complex
osteoporosis: associated with extended therapy (3-6 mo)
heparin chemistry
- straight-chain sulfated mucopolysaccharies produced by mast cells and basophils
- mixture of 5-30 kDa compounds
- extraced from porcine small intestine or bovine lung
- anticoag activity standardized by bioassay
- sulfate groups (negative charge) required for binding to AT
LMWH
2000-9000 daltons
- obtained from depolymerization of unfractionated porcine heparin
- comparison to standard heparin: equal efficacy, increased bioavailability from SQ adm, less frequent dosing - longer t1/2 than heparin, no monitoring of clotting needed
LMWH MOA
- binding AT is sufficient for factor Xa inhibition
- preferentially inhibit factor X
- only slightly affect thrombin activity
- Pt and aPTT are insensitive measures of activity
advantages of LMWH
- more predictable PK profile: good bioavailability from SQ inj site, less protein binding/more uniform dosing, longer half life
- lower incidence oh thrombocytopenia and osteoporosis
fondaparinux
- factor Xa inhibitor
- synthetic sulfated pentasaccharide
- mechanism: indirectly inhibits factor Xa by selectively binding AT
- given SC - can be adm at home
- t1/2: 17 -21 hours (once daily)
- predicatable pharmacokinetics and dose response - does not require monitoring of anticoag effects
- LOW potential for thrombocytopenia
fondaparinux uses
VTE
prophylaxis in patients undergoing hip fracture surgery, hip replacement, knee replacement, or abdominal surgery
orally active factor Xa inhibitors
rivaroxaban
- treatment and prevention of VT and PE
- prevention of thrombosis in NV Atrial Fib
apixaban (eliquis)
-prevention of thrombosis in NV Atrial Fib
both: dose reduction in patients with impaired renal function, increased risk of stroke upon discontinuation
edoxaban (Savaysa)
- treatment of VT and PE after 5-10 days with parenteral anticoag
- prevention of thrombosis in NV Atrial Fib
- renal excretion - not used in patients with CrCl > 95 ml/min
- increased risk of ischemic events upon premature discontinuation
- risk of hematoma/paralysis in patients undergoing spinal puncture or epidural anesthesia
direct thrombin inhibitors
non-heparinoid parenteral agents - do not act through ATIII
-inhibit free thrombin and fibrin-bound thrombin
lepirudin
direct thrombin inhibitor
- recombinant hirudin grown in yeast
- small protein
- highly specific direct inhibitor of thrombin
- irreversible inhibition
- no effect on AT
- aPTT values increase dose-dependently
- excreted via the kidney
- hypersensitivity reaction
bivaliruden (angiomax)
- 20 AA, synthetic peptide
- binds to catalytic site and exosite I of thrombin
- binding is reversible with rapis onset and short duration
- given IV during percutaneous coronary angioplasty
- eliminated by renal excretion
- low risk of bleeding, doesn’t induce Ab formation
argatroban
direct thrombin inhibitor
- binds reversibly to the active site of thrombin
- does not require AT for activity
- can inhibit free & clot-associated thrombin
- therapy monitored using aPTT
- given IV, t1/2 40-50 minutes
- metabolized in liver (CYP3A4/5)
- approved for prophylaxis or treatment in pts w HIT
dabigatran (pradaxa)
- oral direct thrombin inhibitor
- indicated for prevention of stroke and systemic embolism in patients with NV Afib
- eliminated by renal excretion - avoid in cases of severe renal impairment
- laboratory assessment of coagulation state is not required
- actively reversed by praxbind IV
when the BV defect has healed…
the fibrinolytic pathway is activated to dissolve the clot
fibrinolytic pathway
- plasminogen, an anticoag protein, circulated in inactive form and is deposited on to growing clot
- tissue plasminogen activator (a serine protease) can activate plasminogen to plasmin
- plasmin is a proteolytic enzyme that digests firbin and fibrinogen
recombinant tPA
tPA = tissue plasminogen activator
alteplase, reteplase, urokinase
catalyzes plasminogen -> plasmin
streptokinase activator complex
forms with plasminogen to act as plasmin
indications for thrombolytic therapy
- acute MI - initiate ASAP after onset
- acute ischemic thromotic stroke - initiate within 3 hours after onset and exclusion of intracranial hemorrhage
- PE
tpa examples
- binds fibrin and activated bond plasminogen 100x more rapidly than in circulation
- alteplase: human tpa, 527 aa, binds fibrin
- reteplase: human tpa, deletion of aa (355/527), potent, fast, lacks fibrin binding domain - less specific
- tenecteplase - mutant tpa, longer t1/2, IV bolus, fibrin specific
tpa
- IV only
- short duration
- t1/2 = 5-10 min
- clearance by liver and kidney
- AE: bleeding
streptokinase
MOA: forms 1:1 complex with plasminogen to produce an active enzyme complex that catalyzes conversion of inactive plasminogen to active plasmin; does not directly degreade clots - has intrinsic enzyme activity
dosing: IV loading dose to saturate Ab against protein
- AE: bleeding, allergic rxns
urokinase
MOA: 411 AA protease from human kidney cells, directly cleaves plasminogen to plasmin, lacks fibrin specificity
NOT AVAILABLE IN US
anti-fibrinolytic agents
used to stop bleeding caused by thrombolytic agents
aminocaproic acid, tranexamic acid, lysine
-plasmin binds to fibrin through a lysine binding site to activate fibrinolysis
-drugs act as a lysine analog to bind the receptor on plasminogen and plasmin
-the result is a blockade f plasmin to target fibrin
anti-fibrinolytic agents uses and risks
- treat bleeding associated with thrombolytic therapy
- adjunct in hemophilia
- re-bleeding from intracranial aneurysms
major risks: IV thrombosis as result of fibrinolysis inhibition, thrombi formed during therapy are not easily lysed
