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module 2b > 11/4 > Flashcards

11/4 Flashcards

1
Q

Drugs used in coagulation disorders

A

antiplatelets, anticoagulants, thrombolytics, coagulants

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2
Q

hemostasis

A

arrest of bleeding from a damaged blood vessel

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3
Q

coagulation

A

multi-step process to “plug” the leaking vessel

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4
Q

phases of hemostasis

A
  • 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
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5
Q

fibrin clot formation

A

prothrombin -> thrombin

thrombin turns fibrinogen into fibrin

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6
Q

fibrinolysis

A

plasminogen -> plasmin

plasmin facilitates fibrin break down to split products

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7
Q

precursor to platelets

A

megakaryocytes

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8
Q

formation of platelets

A

megakaryocyte -> endomytosis (large and lots of nuclei) -> breakdown of megakayocyte
platelets have organelles and granules but no nucleus

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9
Q

platelets don’t have a ___

A

nucleus - can’t make new enzyme or replicate

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10
Q

contact with ECM initiates platelet reactions:

A
  • adhesion and shape change
  • secretion reaction
  • aggregation
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11
Q

when inserting a catheter into the leg, ___

A

use antiplatelet drugs. The catheter will likely scrape along the endothelium, damage it, expose the ECM and cause clot formation

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12
Q

platelet adhesion to ECM mediated by:

A
  • GP 1a binding to collagen
  • GP 1b binding to von Willebrand Factor bridged to collagen
  • shape change facilitates receptor binding
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13
Q

intact endothelial cells secrete ___ to inhibit ___

A

PGI2 (prostacyclin) to inhibit thrombogenesis (platelet aggregation)

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14
Q

1st step of platelet activation

A

platelet adhesion and shape change

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15
Q

second step of platelet activation

A

platelet secretion

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16
Q

platelet secretion

A

(release reaction)

  • degranulation
  • platelet granules release: ADP, Thromboxane A2 (TXA2), Serotonin (5-HT)
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17
Q

ADP, 5-HT and TXA2

A

released from platelets to activate and secrete other platelets

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18
Q

___ and ___ are potent vasoconstrictors

A

TXA2 and 5-HT

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19
Q

third step of platelet activation

A

aggregation

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20
Q

platelet aggregation

A
  • 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
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21
Q

antiplatelet drugs

A
  • COX-1 inhibitors
  • ADP receptor inhibitors
  • blockers of GPIIb/IIIa receptors
  • PDE3 inhibitors
  • protease-activated receptor inhibitors
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22
Q

COX-1 inhibitor

A

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
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23
Q

aspirin antiplatelet action

A
  • 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
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24
Q

aspirin indications

A

“prophylaxis and treatment of arterial thromboembolic disorders”

  • prevent coronary thrombosis in unstable angina
  • adjunct to thrombolytic therapy
  • reducing recurrence of thrombotic stroke
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25
Q

aspirin clinical actions

A
  • prolongs bleeding time, but no increase in PT time

- hemostasis returns to normal 36 hours after last dose

26
Q

ADP Receptor Inhibitors

A

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
27
Q

thienopyridine class of ADP receptor inhibitors

A

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
28
Q

thienopyridine ADP inhibitor uses

A

acute coronary syndrome, recent MI, stroke, established peripheral vascular disease and coronary stent procedures

29
Q

TTP (thrombotic thrombocytopenia purpura)

A

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
30
Q

prasurgel (effient)

A

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
31
Q

Ticagrelor (Bilinta)

A
  • 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)
32
Q

Cangrelor (Kangreal)

A

P2Y12 ADP inhibitor

  • adjunct to PCI
  • IV
  • reversible inhibitor
  • does not require bioactivation
  • fast onset/ short t1/2 (3-5 min)
33
Q

why does clopidogrel not work well in some patients?

A

activated by CYP2C19 - variable in patients

34
Q

situation cangrelor would be good?

A

if a patient may need to go into surgey

35
Q

Eptifibatide (Integrilin)

A

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

36
Q

Tirofiban (Aggrasat)

A
  • 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
37
Q

Alciximab (ReoPro)

A
  • 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
38
Q

PDE3 inhibitors

A

Dipyridamole, Cilostazol

  • platelet aggregation inhibitor
  • action related to cAMP PDE inhibition (opposing P2Y12 action) and inhibition of adenosine uptake
39
Q

uses of dipyridamole

A
  • combined with warfarin to prevent embolization from prosthetic heart valves
  • with ASA to prevent cerebrovascular ischemia
40
Q

uses of cilostazol

A

intermittent claudication (a peripheral artery disease)

41
Q

protease activated receptor inhibitors

A
  • 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
42
Q

protease activates receptor inhibitor examples

A

vorapaxar - 2014

atopaxar - phase 2 trials

43
Q

Vorapaxar

A 
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
44
Q

vorapaxar CI

A

hx of stroke, TIAs, or intracranial hemorrhage

45
Q

clotting (coagulation) factors

A
  • 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
46
Q

serine proteases

A

-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)

47
Q

glycoproteins

A

-co-factors for activation of proteases
Exmaples: factors VIII, V, III (tissue factor), protein S
-bind to and inhibit thrombin
anti-thrombin III

48
Q

hemophilia A

A

genetic clotting factor disease

  • deficiency in factor VIII
  • 1 in 5,000 males (X linked)
49
Q

hemophilia B

A

genetic clotting factor disease

-deficiency in factor IX - 1 in 25,000 males (X linked)

50
Q

Factor V leiden

A

genetic clotting factor disease

-resistant to activated protein C (~5% of caucasians)

51
Q

where are clotting factors produced?

A

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
52
Q

extrinsic pathway

A

-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

53
Q

intrinsic pathway

A

triggered when collagen is exposed on the wall of the BV

-all components are in the blood (how blood clots in a test tube)

54
Q

activation of the extrinsic or tissue factor pathway to coagulation

A
  • 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)
55
Q

activation of the intrinsic pathway to coagulation

A
  • 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
56
Q

common pathway

A

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
57
Q

lab tests of hemostatic function

A

used for diagnostic purposes or to monitor anticoagulant therapy

58
Q

prothrombin time (PT)

A

recalcified blood + thromboplastin

  • clots in 12-14 seconds
  • monitor oral anticoagulant (warfarin) therapy
59
Q

activated partial thromboplastin time (aPTT)

A

recalcified blood + phospholipid

  • clots in 24-36 seconds
  • monitor heparin therapy
60
Q

bleeding time

A

time take for a standarized skin puncture to stop bleeding
-measured in minutes (2-9)
abnormal when defect in platelet numbers or function

61
Q

procoag factors

A

2, 7, 9, 12

62
Q

anti coag factors

A

protein C to cleave activated 5 and 8

module 2b (9 decks)

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