11/4 Flashcards
Drugs used in coagulation disorders
antiplatelets, anticoagulants, thrombolytics, coagulants
hemostasis
arrest of bleeding from a damaged blood vessel
coagulation
multi-step process to “plug” the leaking vessel
phases of hemostasis
- injury to blood vessel, bleeding occurs
1) vasospasm (constricts BV and flow)
2) platelet plug formation (platelet adherence and aggregation)
3) fibrin clot formation
4) fibrinolysis
fibrin clot formation
prothrombin -> thrombin
thrombin turns fibrinogen into fibrin
fibrinolysis
plasminogen -> plasmin
plasmin facilitates fibrin break down to split products
precursor to platelets
megakaryocytes
formation of platelets
megakaryocyte -> endomytosis (large and lots of nuclei) -> breakdown of megakayocyte
platelets have organelles and granules but no nucleus
platelets don’t have a ___
nucleus - can’t make new enzyme or replicate
contact with ECM initiates platelet reactions:
- adhesion and shape change
- secretion reaction
- aggregation
when inserting a catheter into the leg, ___
use antiplatelet drugs. The catheter will likely scrape along the endothelium, damage it, expose the ECM and cause clot formation
platelet adhesion to ECM mediated by:
- GP 1a binding to collagen
- GP 1b binding to von Willebrand Factor bridged to collagen
- shape change facilitates receptor binding
intact endothelial cells secrete ___ to inhibit ___
PGI2 (prostacyclin) to inhibit thrombogenesis (platelet aggregation)
1st step of platelet activation
platelet adhesion and shape change
second step of platelet activation
platelet secretion
platelet secretion
(release reaction)
- degranulation
- platelet granules release: ADP, Thromboxane A2 (TXA2), Serotonin (5-HT)
ADP, 5-HT and TXA2
released from platelets to activate and secrete other platelets
___ and ___ are potent vasoconstrictors
TXA2 and 5-HT
third step of platelet activation
aggregation
platelet aggregation
- ADP, 5-HT and TXA2 activation induces conformation of GPIIb/III1 receptors to bind fibrinogen
- platelets are cross-linked by fibrinogen
- forms temporary hemostatic plug
- platelets contract to form irreversibly fused mass
- fibrin stablilzes and anchors aggregated platelets
- forms surface for clot formation
antiplatelet drugs
- COX-1 inhibitors
- ADP receptor inhibitors
- blockers of GPIIb/IIIa receptors
- PDE3 inhibitors
- protease-activated receptor inhibitors
COX-1 inhibitor
aspirin
- inhibits platelet COX-1 by acetylation
- interferes with platelet aggregation
- prolongs bleeding time
- prevents arterial thrombi formation
- inhibition of TXA2 synthesis in platelets is the key to anti-platelet activity of ASA
aspirin antiplatelet action
- irreversible inhibition by acetylation of COX-1
- permanent loss of platelet COX-1 activity - decreased TXA2
- maximally effective at dose of 50-320 mg/day
- prostacyclin production tissue inhibited by higher doses
aspirin indications
“prophylaxis and treatment of arterial thromboembolic disorders”
- prevent coronary thrombosis in unstable angina
- adjunct to thrombolytic therapy
- reducing recurrence of thrombotic stroke
aspirin clinical actions
- prolongs bleeding time, but no increase in PT time
- hemostasis returns to normal 36 hours after last dose
ADP Receptor Inhibitors
2 ADP receptors are involved in activating platelets
- P2Y1 (coupled to Gq-PLC-IP3-Ca pathway)
- P2Y12 (coupled to Gi and inhibition of adenylyl cyclase (cAMP))
- activation of both is required for platelet activation by ADP
thienopyridine class of ADP receptor inhibitors
inhibit P2Y12 ADP receptor
- ticlopidine, clopidogrel
- taken orally to reduce platelet aggregation
- irreversibly block ADP receptor on platelet & subsequent activation of GPIIb/IIIa complex
- action lasts several days after last dose
- clopidogrel has lower toxicity profile (ticlopidine may cause TTP
thienopyridine ADP inhibitor uses
acute coronary syndrome, recent MI, stroke, established peripheral vascular disease and coronary stent procedures
TTP (thrombotic thrombocytopenia purpura)
ADAMTS13: protease that cleaves circulating vWF
- ticlid induces abs against ADAMTS12 - decreasing proteolytic activity
- spurious and excessive platelet aggregation
- depletion of platelets
- hemolytic anemia
- renal impairment
- neurological symptoms
- fever
- can be fatal
prasurgel (effient)
thienopyridine ADP inhibitor
- approved for treatment of acute coronary syndone. percutaneous cornoary intervention (PCI)
- oral
- prodrug
- irreversibly bind P2Y12 receptor
- faster onset of action and increased potency due to rapid metabolism by liver CYP450
Ticagrelor (Bilinta)
- inhibits P2Y12 ADP receptor
- not a thienopyridine
- used in acute cornoary syndrome, PCI
- oral
- reversible binding to allosteric site
- does not require bioactivation by metabolic enzymes
- interacts w CYP3A4
- fast onset of actin compared to clopidogrel (t1/2 = 7-9 hours)
Cangrelor (Kangreal)
P2Y12 ADP inhibitor
- adjunct to PCI
- IV
- reversible inhibitor
- does not require bioactivation
- fast onset/ short t1/2 (3-5 min)
why does clopidogrel not work well in some patients?
activated by CYP2C19 - variable in patients
situation cangrelor would be good?
if a patient may need to go into surgey
Eptifibatide (Integrilin)
GPIIb/IIIa inhibitor
-inhibits fibrinogen binding to decrease platelet aggregation
-administration by IV bolus, followed by infusion up to 72 hour
-short duration of actionL 6-12 hours
USE: to prevent thromboembolism in unstable angina & angioplastic coronary procedures
Tirofiban (Aggrasat)
- reversible inhibitor of fibrogen binding to the GPIIb/IIIa receptor
- administered IV in dilute soln
- over 90% inhibition of platelet aggregation after 30 min infusion
- 2 hour plasma half life
- *combined with heparin to treat acute coronary syndrome
Alciximab (ReoPro)
- GPIIb/IIIa inhibitor
- Fab fragment of chimeric human-murine monoclonal Ab
- adm IV blous, followed by infusion (long duration of action - inc risk of bleeding)
- use: prevent thromboembolism in coronary angioplasty
- combined with t-PA for early treatment of acute MI
PDE3 inhibitors
Dipyridamole, Cilostazol
- platelet aggregation inhibitor
- action related to cAMP PDE inhibition (opposing P2Y12 action) and inhibition of adenosine uptake
uses of dipyridamole
- combined with warfarin to prevent embolization from prosthetic heart valves
- with ASA to prevent cerebrovascular ischemia
uses of cilostazol
intermittent claudication (a peripheral artery disease)
protease activated receptor inhibitors
- thrombin activates plateles at nanomolar concentrations
- MOA: proteolytic cleavage of PAR-1 receptors on platelet surface
- RAPs and GPCRs coupled to release Ca from stores
protease activates receptor inhibitor examples
vorapaxar - 2014
atopaxar - phase 2 trials
Vorapaxar
PAR inhibitor -reversible PAR-1 receptor antagonist - PO, QD --prophylactic to prevent thrombosis in patients with a previous MI or peripheral arterial disease (PAD) -used with aspirin or clopidogrel -t1/2 3-4 days -antiplatelet effect persists for days after continuation -metabolized by CYP3A4
vorapaxar CI
hx of stroke, TIAs, or intracranial hemorrhage
clotting (coagulation) factors
- serine proteases
- glycoproteins
- Ca- (factor IV) links certain factors to anioin lipids*critical
- transglutaminase cross-links fibrin fibers (factor XIII)
- fibrinogen/fibrin - the substrate protein factor IIa (thrombin) that polymerizes to form clot
serine proteases
-cleave down-stream factors to activate them
examples (pro-coagulants): factors XII, XI, X, IX, VII, II
-cleave factors Va and VIIIa: protein C (anti-coagulant)
glycoproteins
-co-factors for activation of proteases
Exmaples: factors VIII, V, III (tissue factor), protein S
-bind to and inhibit thrombin
anti-thrombin III
hemophilia A
genetic clotting factor disease
- deficiency in factor VIII
- 1 in 5,000 males (X linked)
hemophilia B
genetic clotting factor disease
-deficiency in factor IX - 1 in 25,000 males (X linked)
Factor V leiden
genetic clotting factor disease
-resistant to activated protein C (~5% of caucasians)
where are clotting factors produced?
all in the liver (except von willebrand factor)
- vWF is produced in the endothelium, subendothelium and megakaryocytes
- factor VIII is also produced in the endothelium
- *liver disease can have unpredictable effects on coagulation
extrinsic pathway
-requires a factor (tissue factor) extrinsic to the blood for activation
-important when vessel is damaged and blood leaks out
-release of tissue thromboplastin initiates pathway
~15 seconds to start clot formation
intrinsic pathway
triggered when collagen is exposed on the wall of the BV
-all components are in the blood (how blood clots in a test tube)
activation of the extrinsic or tissue factor pathway to coagulation
- tissue factor is expressed on the surface of cells outside of but near blood vessels
- factor VII normally resides in the blood
- TF binding to factor VII activates it
- factor VIIa binds and cleaves factor X (interacts w V to convert prothrombin to thrombin; thrombin converts fibrinogen to fibrin)
activation of the intrinsic pathway to coagulation
- factor XII, high molecular weight kininogen (HMWK), and prekallikrein bind to collage on the wall of the damaged blood vessel
- factors XIIa cleaves prekallikrein to kallikrein and factor XI to XIa
- kallikrein activates more factor XII molecules to XIIa
- HMWK achors kallikrein and factor XIa to damaged surface
- factor XIa cleaves HMWK, diffuses into circulation and activated factor IX
- *factor IXa binds factor VIIIA on the surface of platelets and activates factor X
common pathway
extrinsic and intrinsic converge
- prothrombin activator turns prothrombin into thrombin
- thrombin either acts to convert fibrinogen to fibrin or factor XIII to factor XIIIa
- factor XIIIa crosslinks fibrin to form a clot
lab tests of hemostatic function
used for diagnostic purposes or to monitor anticoagulant therapy
prothrombin time (PT)
recalcified blood + thromboplastin
- clots in 12-14 seconds
- monitor oral anticoagulant (warfarin) therapy
activated partial thromboplastin time (aPTT)
recalcified blood + phospholipid
- clots in 24-36 seconds
- monitor heparin therapy
bleeding time
time take for a standarized skin puncture to stop bleeding
-measured in minutes (2-9)
abnormal when defect in platelet numbers or function
procoag factors
2, 7, 9, 12
anti coag factors
protein C to cleave activated 5 and 8
