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Pharmacology 2 > Anticoagulants > Flashcards

Anticoagulants Flashcards

1
Q

Overview of Hemostasis

Platelets ADHERE to subendothelial regions of the injured blood vessel requires (blank)

A

Requires von Willebrand’s factor (VIII:vWF)

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2
Q

Overview of Hemostasis

Local ACTIVATION of plasma coagulation factors requires (Blank)?

A

Requires thrombin (IIa)

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3
Q

Overview of Hemostasis

Platelets AGGREGATE to form primary hemostatic plug requires (blank)?

A

Requires ADP and thrombaxane A2

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4
Q

Overview of Hemostasis

Generation of FIBRIN clot requires (Blank)?

A

Requires the extrinsic, intrinsic and common pathways

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5
Q

Facts about Platelets

A

—-Diameter 80 micromieters ( 2 microns)
—-No nucleus, no DNA, no ability to synthesize proteins or repair damage to themselves(like rbc)
—-Last only a 8-12 days, die
and are eaten by phagocytes
—Produced in bone marrow from disintegration of megakaryoctyes(dev from stem cells of hemocytoblasts)
—-Largest cell present in bone marrow
—-Normal count ~250,000 cells per ml (up to 400,000)
—Approximately 33% of PLT in spleen

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6
Q

MOA that starts the clotting process

A

—Blood vessels lined with overlapping endothelial cells
—These cells cover the entire inner vessel surface
(blood never comes into contact with the vessel wall as long as endothelial lining is intact)
—When vessel CUT it leads to blood contacting other cell types and their contents
—Damaged cells release the protein Collagen

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7
Q

What is collagen’s Role?

A
  • —Coats the outer surface of cells that form vessel walls
  • —Contact with collagen makes platelets sticky and adhere to wall of damaged vessel (VIII:vWF)
  • —Circulating platelets get stuck to other immobilized platelets.
  • –Logjam of plts, crammed into the hole
  • –All stuck to each other, except for those on the edges, which are glued to the vessel wall
  • –THIS MASS IS THE PLATELET PLUG
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8
Q

What happens in the platelet plug, after collagen has been release?

A

—-Platelets in the plug begin to contract and pull the edges of the hole closer together so a tissue bridge can form and permanently seal the leak

–ONLY NOW DOES A CLOT FORM

—Platelets provide the anchor for clot adherence

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9
Q

When an injury occurs that punctures a blood vessel but doesn’t break or tear the vessel,
(BLANK)
form the body’s 1st line of defense

A

When an injury occurs that punctures a blood vessel but doesn’t break or tear the vessel,
PLATELETS
form the body’s 1st line of defense

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10
Q

What is the contractility of blood vessel walls and platelets that pull edges of wound together and hasten permanent repair???

A

Contractility of

blood vessel walls and platelets
pull edges of wound together
and hasten permanent repair

Primary long term sealant is a blood clot

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11
Q

What are the Vitamin K dependent factors???***

A 
Factors:**
II  Prothrombin (liver)
VII Proconvertin
IX  Christmas Factor (liver and other tissues)
X Stuart Prower Factor  (liver)
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12
Q

How fast does the Extrinsic pathway take?

A

Initiates in 15 sec.

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13
Q

How fast does the Intrinsic pathway Take?

A

Slower when compared with Extrinsic pathway, onset 2-6 minutes

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14
Q

Damage within what system will start the Intrinsic pathway?

A

Damage within the circ. System

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15
Q

Damage where? will start the Extrinisic pathway?

A

Followed when there is fairly extensive tissue damage, result of cuts or tears in vessels.

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16
Q

What are the steps of the common pathway?

A

Clotting

  • –2 activation cascades both convert X to Xa
  • –Xa, with Va, activates prothrombin (II) to thrombin (IIa).
  • –Thrombin activates fibrinogen (I) to fribrin (Ia).
  • –Fibrin aggregates forming multitudes of fibers that form a soft clot
  • -Transglutaminase cross-links fibrin threads to yield a hard clot
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17
Q

What is Fibrinogen?

A

Fibrinogen (I) is soluble

  • –Normally, charge repulsions prevent fibrinogen from self-associating, thus, individual molecules remain soluble in the circulating blood
  • –Thrombin (IIa) converts fibrinogen to fibrin by cleaving fibrinopeptides altering the charge (the opposite charge attracts)
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18
Q

What is Fibrin?

A
  • –Fibrin (Ia) is insoluble and aggregates to yield a soft clot
  • –Fibrin forms a threadlike fibrin aggregates
  • –Traps platelets and other debris
  • —Soft clot is not stable (held together by electrostatic charges)
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19
Q

With the conversion of Fibrinogen to Fibrin, how is the soft clot cross-linked by?

A

Soft clot is cross-linked by factor XIIIa with Ca++ to yield hard clot fibrin fiber*

Factor XIIIa (transglutaminase) forms peptide bonds stabilizing and strengthening each fibrous thread

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20
Q

How is Prothrombin converted to Thrombin?

A

Factor Xa cleaves two peptide bonds in prothrombin (II) to form thrombin (IIa)

Activation of prothrombin (II) by Xa is accelerated by Va, phopholipids and Ca++

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21
Q

What are the Zymogens of the Intrinsic pathway?

A 
Intrinsic pathway
XII Hageman factor
XI Plasma Thromboplastin
IX Christmas factor
VIII:C Antihemophilic factor (VIII:vWF von Willebrand’s factor)
IV Ca++
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22
Q

What are the Zymogens of the Extrinsic pathway?

A

Extrinsic pathway
VII Proconvertin
III Tissue Factor Thromboplastin
IV Ca++

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23
Q

What are the Zymogens of the Common pathway?

A 
Common pathway
X Stuart factor
V Proaccelerin
II Prothrombin – IIa Thrombin
I Fibrinogen – Ia Fibrin
XIII Fibrin Stabilizing Factor
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24
Q

How is the Intrinsic Pathway initiated?

A

Trauma to the blood itself or exposure of the blood to collagen in a traumatized blood vessel wall activates factor XII. XIIa activates factor XI. XIa activates factor IX. IXa, when complexed on the platelet surface with activated factor VIII:C and Ca++, activates factor X (Xa).

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25
Q

How is the Extrinsic Pathway initiated?

A

Damage outside of blood vessels triggers the release of thromboplastin (III) from damaged cells. IIIa activates factor VII. VIIa when complexed on the surface of the platelet with Ca++ and IIIa, activates factor X

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26
Q

How is the Extrinsic Pathway tested?

A

Coumadin PT, INR

International normalized ratio (INR)

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27
Q

How is the Intrinsic Pathway tested?

A

Heparin aPTT and ACT

Activated clotting time (ACT)

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28
Q

How is the Common Pathway initiated?

A

Xa, when complexed on the platelet surface with Va, and IV, converts prothrombin (II) to thrombin (IIa). IIa converts fibrinogen (I) to fibrin (Ia) and in the presence of factor XIII, fibrin cross-linking occurs

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29
Q

How is the clot formation stopped in the clotting cascade?

A

—Stopping Clot Formation
Anti Thrombin III (AT III) ( they dropped the III, so we just call it anti thrombin) binds irreversibly to thrombin (IIa) (this happens so the clot doesn’t have the ability to go somewhere else)
—AT III also binds to IXa, Xa, and XIa of the intrinsic pathway

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30
Q

How is the dissolution of the clot occur?

A

Dissolution of Clot

  • –Tissue Plasminogen Activator activates plasminogen (is incorporated into the clot as it is formed aka tPA, or uPA) (this is a self destruction process, it just takes a long time) to plasmin
  • –Plasmin hydrolyzes (breaks) the fibrin to peptides…(and this will then get filtered out)
  • -(clot will go away in 7-10 days)
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31
Q

How does the body protect a clot?

A

Protecting the Clot

-Antiplasmin inhibits fibrin hydrolysis

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32
Q

How does the body prevent the clot from forming?

A

Preventing Clot Formation

  • -Heparin acts as a catalyst for inactivation of thrombin by antithrombin III
  • -Citrate acts to chelate Ca++ (this is in blood products)
  • -Oxalate also chelates Ca++
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33
Q

What is Antithrombrin III?

A
  • –Antithrombin III is always present in serum
  • –Binding between AT III and Thrombin (IIa) prevents thrombin from proteolytically activating fibrinogen (I) to fibrin (Ia)
  • -AT III strongly inhibits IIa and Xa
  • -AT III partially inhibits factors IXa, XIa, and XIIa
  • -AT III counteracts any unscheduled clot formation
  • -Impact injury triggers clotting at the injury-site by activating thrombin
  • -Any thrombin that might escape the local clot is inactivated (by AT III), thus, clotting does not spread throughout the body
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34
Q

What are natural anticoagulant mechanisms?

A

Prostacyclin

  • -A metabolite of arachidonic acid
  • -Synthesized by the endothelial cells
  • -Inhibits platelet aggregation

Antithrombin

  • -Plasma protein
  • -Inhibits coagulation factors of the intrinsic and common pathways

Heparan Sulfate Proteoglycans

  • -Synthesized by endothelial cells
  • -Stimulates the activity of antithrombin

Protien C

  • -When activated by thrombin, degrades cofactors Va and VIIIa
  • -Greatly diminishes activation of prothrombin and factor X

Tissue Factor Pathway Inhibitor

  • -Found in lipoprotein of plasma
  • -When bound to factor Xa, TFPI inhibits factor Xa and factor VIIa
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35
Q

Where is Heparin stored in the body?

A

Heparin is stored in the mast cells

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36
Q

What is the structure of Heparin in the body?

A

Heparin is a negatively charged Mucopolysacharide

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37
Q

Does Heparin cross the placenta?

A

Heparin does not cross the placenta

38
Q

Heparin in the body, inhibits what apart of the clotting cascade?

A

Thrombin (IIa) and factor Xa are inhibited

39
Q

Heparin in the body, how does it work as an anticoagulant?

A

Heparin acts as an anticoagulant by binding to ATIII enhancing the rate of thrombin AT III complex formation by 1,000 to 10,000 times

Acts as a catalyst

40
Q

Where is unfractionated heparin extracted from?

A

Unfractionated heparin (UFH) is an extract of porcine intestines or bovine lung

41
Q

What are some clinical uses for Heparin?

A 
Venous Thrombosis 
Pulmonary embolism 
Unstable angina/MI
Coronary angioplasty or stent placement 
DIC
42
Q

How is Heparin metabolized?

A

Metabolism: Liver & reticuloendothelial system (part of immune system)

43
Q

What are the two mechanisms in which Heparin is removed from the blood?

A

Saturable & Non-Saturable

44
Q

What is the Saturable mechanism in which Heparin is removed by the blood?

A

Saturable-represents clearance by the reticuloendothelial system and endothelial cells to which heparin binds with a high affinity

45
Q

What is the Non-saturable mechanism in which Heparin is removed by the blood?

A

Non-saturable-represents renal excretion
Low dose heparin removed by saturable mechanism
High dose heparin removed via nonsaturable mechanism

46
Q

What does aPTT stand for?

A

Activated partial thromboplastin time (aPTT)

47
Q

Which laboratory test does Heparin prolong?

A

Heparin prolongs aPTT

48
Q

What is the range for an aPTT? with Heparin

A
  • -Heparin tx is usually monitored to maintain the ratio of the aPTT within a defined rage of approximately 1.5 to 2.5 times normal value
  • -Typically 30 -35 seconds

*** easily corrected by omitting a dose due to brief half life ( 23 min to 2.48 hr) (book says 1hr to 1 ½ hr) we will go with that number

49
Q

What does ACT stand for?

A

Activated Clotting Time

50
Q

When do you use an ACT?

A

At high heparin concentration the ACT is used to monitor anticoagulation

51
Q

How does ACT work?

A

Performed by mixing whole blood with and activating substance that has a large surface area such a celite
Influenced by (affected by):
Hypothermia
Thrombocytopenia
Presence of aprotinin
Preexisting coagulation deficiencies (fibrinogen, factor XII and factor VII)

52
Q

What are the clinical use of ACT?

A
  • –During Cardiopulmonary bypass the target ACT value is still controversial but considered adequate if the ACT is longer than 350 seconds
  • –The need to measure ACT repeatedly is emphasized by the variations of heparin sensitivity between patients and variation in heparin metabolized
53
Q

What is HIT???

A
  • -HIT is an “”anti-body mediated reaction”” in which heparin administration causes a person to enter a pathological and highly prothrombotic state (you begin to clot)
  • –Thrombocytopenia due to UFH is common and “can begin within hours in pt. exposed to heparin”
  • –HIT occurs in approximately 0.5% -5% of those exposed to heparin manifest as severe thrombocytopenia ( 50% drop in platelet count or <100,000cells/mm3 *
54
Q

HIT develops which king of antibodies?

A
  • –Development of IgG antibodies against complexes of heparin with platelet factor 4
  • –These complexes activate platelets which results in platelet aggregation and thrombin generation (you will be using up you platelets to for clots, so count will drop)
  • –Heparin should be D/C immediately
  • –An alternate anticoagulant should be administered
  • -Lepirudin or danaparoid
  • -Warfarin may cause venous limb gangrene or multicentric skin necrosis.
55
Q

What platelet count would indicate HIT?

A

Platelet count < 150,000 or 50% less than baseline

56
Q

About how many days will HITT occur?

A

Severe response typically develops after 4-5 days of heparin therapy

57
Q

What is HITT?

A

Heparin-induced thrombocytopenia with thrombosis HITT

58
Q

What is the treatment of HIT?

A
  • –Suspend use of all heparin ( flush and tubing)
  • –Suspend use of vitamin k antagonist
  • –Begin alternative anticoagulant therapy
  • –Investigate lower-limb DVT (because of the prothrombic state)
  • –Upon recovery of platelet count restart vitamin K antagonist
  • –Avoid prophylactic platelet transfusion they can cause increase thrombogenic effect (more platelets will make it worst) (need to find other means to anticoagulate the patient)
59
Q

What do you use to reverse Heparin?

A

Protamine used for reversing anticoagulation

Protamine found in salmon sperm

60
Q

What is the dose for Protamine?

A

Dose of protamine required to antagonize heparin is typically (1mg for every 100units) of circulating heparin activity

61
Q

How does Protamine reverse Heparin?

A

How: “+ charged alkaline” protamine combines with the - charged acid heparin to form a stable complex that is devoid of anticoagulant activity

62
Q

What are the side effects of Protamine?

A

Protamine Side Effects**

  • –Hypotension (histamine release) ** (when you give large amounts of it)
  • -Pulmonary Hypertension (release of thromboxane/serotonin) ***
  • -Allergic reaction** (NPH?)
63
Q

Does Protamine work on LMWH?

A

Protamine does not neutralize LMWH** (because it is a fraction) this is weaker than the parent compund

64
Q

How is LMWH removed from the blood?

A
  • -LMWH mainly removed by non-saturable renal excretion

- –Effect prolonged with renal failure

65
Q

What are the doses for Enoxaparin and Dalteparin?

A 
Low Molecular Weight Heparin 
Enoxaparin 30mg SC q12h 
Enoxaparin 40mg SC q24h 
Dalteparin 5,000 units SC q24h 
Dalteparin 2,500 units SC q24h
66
Q

If someone is on LMWH, how long do you need to delay a needle placement for a spinal or epidural?

A

Delay needle placement for a minimum of 12 hours

Pre-operative LMWH is not recommended with neuraxial procedures.

67
Q

What is Fondaparinux?

A
  • -Synthetic anticoagulant
  • –Inhibits factor Xa (more selective) but no direct activity against thrombin
  • -Administer SQ
  • –Elimination half life 15 hours (good because you can give once a day)
  • –Eliminated by kidneys-use with caution in renal failure
  • –Clinical Use: DVT, PE, Alternative for pt. with HIT
68
Q

Why is warfarin the most frequently used anticoagulant?

A
  • –Vitamin K Antagonists
  • –Oral anticoagulants are derivatives of 4 hydroxycoumarin
  • -**Warfarin is most frequently used anticoagulant because of its predictability onset and duration of action and its excellent bioavailability after oral administration (takes 3-5 days for it to work) (what ever is in the body wont be affected, its what will be created is what will be affected)
69
Q

What are some disadvantages of Warfarin?

A
  • –Delayed onset of action
  • –Need for regular laboratory monitoring
  • –Difficulty in reversal should a surgical procedure create concern about bleeding
70
Q

What is the mechanism of action for Warfarin?

A

—Inhibits vitamin K epoxide reductase that converts the vitamin K dependent coagulation proteins (2,7,9, 10)
—-Anticoagulant effect delayed for 8 to 12 hours
+++Pharmacokinetics
–Complete absorption within 1 hour
—-Does cross the placenta (not good for pregnancy)
–Ultimately excreted in bile

71
Q

What is the Lab evaluation for warfarin?

A
  • –Treatment with oral anticoagulants is best guided by Prothrombin time (PT)
  • INR addresses the problem of variability
  • –INR is the ratio of a patients prothrombin time to a normal control
  • –Most indication a moderate anticoagulant effect with a target INR
  • –2.0 to 3.0 is appropriate
  • –Unexpected fluctuations in the dose respond to warfarin may reflect change in died
72
Q

What are some clinical uses for VKAs?

A 
VKAs effective-
Prevent:
Embolization
Heart valve
Atrial fibrillation
73
Q

Management of elective surgery and warfarin.

A

—Emergency situation oral or IV administration of Vitamin K
—Will not immediately reverse anticoagulant effect**
—FFP (will not reverse immediately)
(will take about 3-5 days to come off, just like it takes to therapeutically work)

74
Q

What factor does Xarelto (Rivaroxaban) on?

A

Direct Factor Xa

75
Q

What factor does Pradaxa (Dabigatran Etexilate) work on?

A

Direct thrombin inhibitor

76
Q

How does Aspirin work?

A

Aspirin

  • –Blocks production of thromboxane A2
  • –Since platelets do not synthesize new proteins, the action of ASA on platelet cyclooxygenase is permanent lasting the life of the platelet (7-10 days)
  • –Complete inactivation is achieved with 160 mg/day
77
Q

What receptor does Plavix work on and how?

A

Plavix

  • -Work at the G protein receptors
  • -Inhibits adenylyl cyclase which results in lower levels of cyclic AMP and thereby less platelet activation**
78
Q

What is the dose for Ticlid?

A

Ticlid loading 500 mg followed by 250 mg/day

Inhibition of platelets persists for 3-4 days after D/C

79
Q

What is the dose for Plavix?

A

Plavix loading 300 mg followed by 75 mg/day

Inhibition of platelets persists for 3-4 days after D/C

80
Q

What are the adverse effects for ticlid and plavix?

A

Adverse effects
Nausea, vomiting and diarrhea
Neutropenia

81
Q

What are Glycoprotein IIb/IIIa Inhibitors?

A

—Platelet surface integrin
—Glycoprotein is a receptor for fibrinogen and von Willebrand factor which anchor platelets to foreign surfaces and to each other, thereby mediating aggregation*
—The receptor is activated by platelet agonists
Thrombin, collagen, or thromboxane A2
——Inhibition of the glycoprotein binding blocks platelet aggregation induced by any of the agonist*
Examples Reopro, Integrilin

82
Q

What is Fibrinolysis?

A

Fibrinolysis (clot busting role of plasmin)

  • -After a clot is formed and hemostasis is accomplished, the clot needs to be broken down.
  • -Plasminogen, the inactive form of plasmin, is synthesized in the liver, circulates in the blood, and is incorporated into the clot
  • -Plasminogen activators convert plasminogen to its active form plasmin
  • -Plasmin breaks down fibrin
83
Q

What is Tissue-type plasminogen activator (tPA)

A

Tissue-type plasminogen activator (tPA)

  • -Incorporated with fibrin in the forming clot
  • -Produced by endothelial cells and released into circulation
  • -Release is stimulated by thrombin and venous stasis
  • -By binding to fibrin, converts plasminogen to plasmin
84
Q

What is Urokinase-type plasminogen activator (uPA)

A

Urokinase-type plasminogen activator (uPA)

  • –Found in limited amounts in the blood
  • -Has little affinity for fibrin
  • -The most widely used agent fro intra-arterial infusion into peripheral arterial system and grafts
85
Q

What is Streptokinase?

A

Streptokinase

  • -Produced by beta-hemolytic streptococci
  • -Has little affinity for fibrin
  • -Preformed antibodies may inactivate streptokinase
86
Q

What are some contraindication to thrombolytic therapy?

A

Surgery within 10 days

  • -Organ biopsy, puncture of noncompressible vessel, serious trauma, cardiopulmonary resuscitation
  • -Serious GI bleeding within 3 months
  • -History of HTN (DBP > 110 mm Hg)
  • -Active bleeding or hemorrhagic disorder
  • -Previous CVA or active intracranial process
  • -Aortic dissection
  • -Acute pericarditis
87
Q

What is Amicar?

A

Amicar (Antifibrinolytic Agents)

  • –Prevents the breakdown of fibrin by preventing the attachment of plasmin to fibrin
  • -Beneficial in the control of hemorrhage associatd with primary fibrinolysis caused by increased plasminogen activation
88
Q

What is Aprotinin?

A

Aprotinin (Antifibrinolytic Agents)

  • -Inhibits plasmin, therefore fibrin breakdown is slowed.
  • -Used during cardiac surgery to decrease intraoperative blood loss
89
Q

What are some Botanical (salicylate Or anti platelet) agents?

A 
Agrimony
Aloe gel
Aspen
Black Cohosh
Black Haw
Bogbean
Cassia
Clove
Dandelion
Feverfew
Garlic
German Sarsaparilla
Ginger
Ginko
Ginsing
Licorice
Meadowsweet
Onion
Policosanol
Poplar
Senega
Tamarind
Willow
Wintergreen
90
Q

What are some Botanicals w/ fibrinolytic properties?

A 
Bromelains
Capsicum 
Garlic
Ginseng
Inositol Nicotinate
Onion

Pharmacology 2 (11 decks)

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