Cardio Test 3 Dr. G

Front 1

What is hemostasis?

Back 1

Bodies natural process of stopping bleeding from an injured blood vessel

Front 2

What are the body's 2 primary hemostasis mechanisms?

Back 2

1. vasospasm
Vasoconstriction of BV modulated by TXA2, & 5-HT
Slow down the bleeding

2. platelet plug
Adherence of platelets to collagen of damaged endothelium. Role of thrombin, ADP, TXA2, 5-HT, & Prostaglandins

Front 3

What are the body's 2 secondary hemostasis mechanisms?

Back 3

1. Fibrin clot:
Conversion of prothrombin to thrombin. Thrombin stimulates the conversion of fibrinogen (blood protein) to fibrin (mesh)

2. Dissolution of the clot (fibrinolysis):
Plasminogen is converted to plasmin, the enzyme that dissolves the fibrin

Front 4

what is a red clot?

Back 4

Once that fibrin forms on the platelet

now it is a stable clot that is a hard plug and will stop any more hemorrhage from occurring in that vessel

fibrin in place and solidify that clot

Front 5

what is a white clot?

Back 5

when you have platelets and fibrinogen and they are just
platelet aggregation

coming together and are mushy, doesn’t have a lot of structure and easy to be yanked out

Front 6

what does fibrin do to clots?

Back 6

that’s what hardens it and causes bond btw platelets

You have to convert fibrinogen to fibrin in order to harden that clot

Front 7

what does plasmin do to clots?

Back 7

what breaks clot down

Front 8

What does an increase in Ca++ do to platelet aggregation?

Back 8

So as you increase calcium inside the platelets, you will produce more receptors and release more ADP and TXA2 which will  in turn cause more platelets to aggregate and now the white clot will form.
If you look at ATX2 receptors, alpha 1 receptors, or serotonin receptors, whichever one that NE is bound to, all those  receptors are coupled to Gq and b/c they are coupled to Gq, they will cause an increase in Ca++ inside of the cell.

Front 9

What are the 5 components/stages of a fibrin clot?

Back 9

1.Organizing surface
2.Precursor protein
3.Protease from the preceding stage
4.Non-enzymatic protein cofactors
5.Phospholipids & Ca++

Front 10

what do anti-thrombin and protein C &S do?

Back 10

These are drugs that cause a decrease in coagulation (anti-coagulating agents).
This is incase you have overcoagulation.

Front 11

which signals can cause t-PA release?
What does t-PA ?

Back 11

NO, prostaglandings and healthy endothelliums can release chemicals that can facilitate the breakdown and release of t-PA

t-PA binds to plasmininogens and cause its conversion from plasminogens to plasmin and thus faciliate breakdown of clotting

Once you have healing of tissue: TPA comes in and breaks fibrin down and then it can be removed from system

Front 12

What does Heparin do?

Back 12

can bind to anti-thrombin and facilitate it’s activity , affinity or efficacy in binding to Xa, or IIa and thus inhibiting the clotting cascade.

Front 13

what does Dabigatran do?

Back 13

direct thrombin inhibitor, by binding to thrombin it can inactivate it and thus it can’t convert fibrinogen to fibrin( so can’t get the hard clot).

Front 14

what do t-PA analogues do?

Back 14

alteplase: break clots in case you have something lodged in the artery or veins in lungs, brain or heart

Front 15

what does Aspirin do?

Back 15

blocks or slows down platelet aggregation

Front 16

what does warfarin do?

Back 16

causes inhibition of vit. K- reductase and can deplete a number of those cofactors( VIIa,Xa, IIa,IXa,etc.)

Front 17

What is the intrinsic pathway, extrinsic pathway, and where do they meet?

Back 17

Intrinsic pathway (components are within the blood)
VII→VIIa
II→ IIa

Extrinsic pathway (components are outside of the blood)
IX(9) →IXa
They meet half way on the precursor number 10 (called common pathway)

Front 18

What is the common pathway?

Back 18

10 →10a, 10a activates 2 (prothrombin) →2a (thrombin) → thrombin can activate fibrinogen (which is linking the platelets together) → fibrin → hardens →red clot

Front 19

What is thrombin and what number is it?

Back 19

Thrombin is IIa (and it's precursor Prothrombin (II): Converts fibrinogen (I) to fibrin (Ia) monomers by cleaving fibrinopeptides A & B. This allows fibrin to form a gel

Front 20

What is Cofactors Va ?

Back 20

V: present freely in plasma & as a component of platelets. It is converted to Va by thrombin, which increases by 50X the coagulation activity of Xa
Thrombin (IIa)→ Va →(50x↑) →Xa

Front 21

What is cofactor Xa?

Back 21

Common pathway
10→10a
or IIa (thrombin) → Va → 10a

Front 22

What is Tissue Factor (TF)?

Back 22

Non-enzymatic lipoprotein cofactor that greatly increases the proteolytic efficiency of VIIa. VIIa activates factor X
Present in the surface of cells that do not normally contact plasma (EXTRINSIC)

Front 23

What is Antithrombin?

Back 23

is a plasma protein that inhibits aggregation factors Xa and IIa (thrombin)
Heparan sulfate is a proteoglycan synthesized by the endothelium cells and stimulate the activity of antithrombin (ANTICOAG)

Front 24

What is Protein C and S?

Back 24

degrades cofactors Va and VIIIa, which leads to the decrease in prothrombin (II)and factor X activation (ANTICOAG)

Front 25

What do prostaglandins and NO do to platelet aggregation?

Back 25

Prostaglandins (PGI2) & NO inhibit platelet aggregation
**but these patients can't vasodilate because they have hardened arteries due to plaque buildup)

Front 26

In vitro coagulation process and purpose

Back 26

Blood is mixed with a chelating agent EDTA (anticoag)

It is a standard measure of pt coagulation time to estimate in vivo coagulation (ex: PT/INR time)

measure aPTT: Intrinsic Pathway: measures how HEPARIN is working

measure PT: Extrinsic common pathway: measures how WARFARIN is working

Important: to know how to dose the medication

Front 27

What does it mean to have a HIGH PT time (30-40 seconds to coagulate) , if your patient is taking Warfarin?

Back 27

Your blood is too thin and you are inhibiting coagulation too much
**need to DECREASE the dose**

Front 28

What does it mean to have a LOW PT time (20 seconds) if on Warfarin?

Back 28

it takes a very short time for your blood to coagulate so this means that your dose is too small

**need to INCREASE the dose**

Front 29

Heparin Sulfate
where is it found?
how does it work?

Back 29

naturally occuring endogenous compound and produced and secreted by mast cells (immune response in Lungs, Skin, Intestine) and basophils

works as an allosteric agonist – enhances ability of antithrombin to do its job

enhances ability of antithrombin to bind to Xa & IIa active proteases and inhibit them nonselectively

Front 30

Heparin Na+ and Ca++ (Unfractionated: large g/mol molecule)
MOA

Back 30

Heparin is an allosteric agonist, and makes antithrombin work much better at binding to Xa or IIa and inhibiting that pathway

Official MOA: Increase the rate of thrombin-antithrombin reactions by making the reactive site more accessible to the protease. Thrombin inactivation

Either directly you DIRECTLY block formation of thrombin (IIa) or you INDIRECTLY inhibit thrombin from activating fibrinogen (I) into fibrin (Ia) (RED CLOT)

You still have Va, but its not enough to accelerate reaction from II (prothrombin) → IIa (thrombin) : by slowing down this rate of reaction you will have less coagulation → thinner blood, but still a little coagulation via Va

Front 31

What is the onset of action of Heparin? Why is it so fast?

Back 31

30-60 minutes

Heparin works fast (fast onset) b/c working on the common pathway but also b/c antithrombin is already in blood & doesn’t have to be made, **main reason is because it works on activated factors. It just has to bind to activated factors and inhibit them from doing there job. Onset of action for heparin is pretty fast, it’s binding to things already made & doing something to system – block reaction from occurring by blocking activated factors.

Front 32

What is the antidote for Heparin over dose?

Back 32

Protamine sulfate
(+ charges that binds ionically to heparin)

Front 33

What are DDIs of Heparin?

Back 33

Any drug that may increase the risk of bleeding (salicylates)
Recent trauma, peptic ulcer, etc

Front 34

What are the adverse effects for Heparin?

Back 34

1. Bleeding

2. HAT (decrease in platelet levels: non-immune mediated)

3. HIT (decrease in platelet levels: immune mediated)

Front 35

What is the difference between HAT and HIT?

Back 35

1. Heparin Associated Thrombocytopenia (HAT)
Transient fall in platelet count
starts 2-4 days into heparin therapy
- NOT antibody mediated
mediated….mechanism unknown
-Heparin use may be continued

2. Heparin-induced thrombocytopenia (HIT)
-0.5% after 5-10 days
- anti-body mediated against heparin
-against platelet factor 4 (PF4)
-Leads to platelet aggregation, release of more PF4 and thrombin generation
-HAVE INCREASED RISK FOR THROMBOTIC EVEN DESPITE SEVERE THROMBOCYTOPENIA (HIT is more serious)


**If pt develops HIT or HAT – you have to immediately stop heparin, could be life-threatening situation

Front 36

Low- MW- Heparins (FRACTIONATED)
MOA
PK
Side Effects
Contraindications
Antidote if overdose

Back 36

MOA: Inhibits factor Xa only, very little effect on factor IIa

Advantages:
-Less incidence of HIT
-Outpatient Setting (PK)
-Lower incidence of Bleeding

PK:
-can be give Subcutaneous or IV
-immediate onset (30-60 min)

Side Effects:
Thrombocytopenia, or bleeding

Contraindications: existing bleeding condition

If OD: Protamine Sulfate

Front 37

What are 3 Low MW- Heparin examples?

Back 37

1. Enoxaparin (Lovenox)
2. Dalteparin (Fragmin)
3. Ardeparin, Nadroparin, Reviparin

Front 38

What type of drug is Fondaparinux (Anixtra)?
What is its benefit?

Back 38

Synthetic heparin that binds antithrombin to Xa ONLY (which blocks II (prothrombin)→IIa (thrombin) only
Benefit:
-Less likely to produce HIT
-less incidence of bleeding cause only effecting one part of the pathway (10a). Not effecting IIa directly
-Still get Fibrinogen (I) → Fibrin (Ia) pathway via Thrombin (IIa)

Front 39

What is the difference between fractionated heparin and unfracitonated heparin?

Back 39

-Unfractionated heparin is going to effect both Xa and IIa
-Fractionated or synthetic heparin is going to effect Xa

Front 40

What are Direct Thrombin Inhibitors?
What are 5 examples?

Back 40

Directly bind to thrombin (IIa) & inhibit it’s ability to cleave fibrinogen (I) into fibrin (Ia)

1.Lepirudin
-Irreversible binding Recombinant derivative of hirudin.

2. Bivalirudin
-Reversible binding
Synthetic that is reversible by thrombin bond cleavage

3. Argatroban
-Reversible binding
Synthetic compound based on the structure of L-Arginine that binds reversibly to the catalytic site of thrombin

4. Dabigatran (warfarin replacement drug)

5. Warfarin??
**First 3 drugs all IV but not used very often due to better choices**

Front 41

How does Dabigatran work?
What are it's benefits?

Back 41

Direct Thrombin Inhibitor (IIa)

Benefits:
1. Oral – can give in out-pt setting
2. No measurement of blood draws
-No INR labs like warfarin
3. No known DDI (Warfarin interacts with almost everything)
-Not metabolized by CYP450 (so don’t have to worry about other drugs that inhibit or induce it)
- Less HIT, HAT
- Works fast (works on enzymes already made)

Front 42

What is the MOA of Warfarin?
What factors does it affect?

Back 42

It inhibit the vitamin K epoxide reductase.
Activation of coagulation factors II, VII, IX, and X and anticoagulant protein C & S requires CO2, O2, and reduced vitamin K.

-Blocks all these factors (by 50%) because it blocks Vit K which produces these factors:
VII, IX, X, II, protein C, protein S

Front 43

Why does it take a long time for Warfarin to work?

Back 43

Remember: heparin works on activated factors
Warfarin: Has to exhausts vit K first which takes 3 to 5 half lives
Warfarin takes about 3-7 Days to work

Another problem: warfarin can inhibit protein C & S
Function of protein C & S – Anti-clotting factors
b/c half life is smaller, need to start heparin first & then warfarin

start on low dose of heparin & start on warfarin
Once warfarin starts working then take them off heparin
Warfarin will inhibit protein C&S too fast b/c of short T1/2 and you will cause the system to coagulate more before you exhaust the other factors
So that’s why you should start on heparin first, to stop it from coagulating too fast.

Front 44

Why must you take Heparin simultaneously with Warfarin?

Back 44

-1) Warfarin takes a while to start working.
2) Heparin can help override the initial clot evoked by Protein C &S inhibition


Because Inhibits protein C & S – half lives are shorter, so stop anticoagulating & coagulate too fast →side effect w/in first couple days of therapy.

Front 45

Warfarin DDIs
why is there a DDI?

Back 45

Any drug that alter the
1. Uptake or metabolism of warfarin or vitamin K

2.Synthesis, function or clearance of any factor or cell involved in hemostasis or fibrinolysis

3. Integrity of any epithelial surface

These drugs/food alter the PT time (time it takes to clot)
-If you ↑ PT time = longer to clot = ↑ bleeding (ex: antibiotics, etOH, supplements

- If you ↓ PT time = shorter time to clot = ↑ clot (ex: vit K)

Front 46

Warfarin Side Effects

Back 46

1. Hemorrhage
2. Teratogenic
3. Skin necrosis
4. Purple toe syndrome

Front 47

What is the antidote in Warfarin over dose?

Back 47

Vitamin K

Front 48

What is the difference between Warfarin and Heparin?

Back 48

WARFARIN acts SLOWLY because it is affecting the SYNTHESIS of factors whereas HEPARIN acts RAPIDLY because it is INACTIVATING factors that are already circulating

-Warfarin can be taken orally while Heparin is IV or SC

OD:
Warfarin: stop drug and give vitamin K
Heparin: stop drug and give protamine sulfate

Primary ADR for both:
Hemorrhage

Front 49

How do Fibrinoltic drugs work and when do you use them?

Back 49

They ACTIVATE plasminogen (bound to fibrin) and increases plasmin levels (plasmin BREAKS down clots, so you want it)

If you have MI, stroke and have to break clot to decease damage of tissue, this is time dependent (less than 5 hrs after)

Front 50

What is the antidote for Fibrinolitic drugs (drugs that break down clot ie: alteplace, retaplase, urokinase, streptokinase)

Back 50

Aminocaproic acid
-inhibits fibrinolysis by competitively blocking plasminogen activation

Front 51

What is the MOA of t-PA, Alteplase, Reteplase?

Back 51

MOA: It is a serine protease which ACTIVATES plasminogen (bound to fibrin) and INCREASES plasmin levels (plasmin breaks down clots). Clot specific and must bind to fibrin
-It activates bound plasminogen (must be bound) several hundredfold
-It is effective in lysing thrombi during treatment of acute MI

Front 52

What is the MOA of Urokinase and Streptokinase?

Back 52

These drugs are NOT clot specific so not used often

strepto/urokinase = doesn’t matter if plasminogen is bound or not, It can still convert plasminogen to plasmin
Urokinase
MOA: Directly activates plasminogen; isolated from human kidney, therefore less chance of evoking an allergic reaction

Streptokinase:
MOA: Combines with plasminogen to form an active complex that converts plasminogen to plasmin to dissolve the fibrin

Front 53

What are the ADR and DDI and contraindications of Strepto & Urokinase?

Back 53

ADR
Hemorrhage
DDI
Increases risk of bleeding with dicumarol, warfarin, heparin, aspirin, ticlopidine, abciximab.
Contraindications:
anything to do with bleeding ex: trauma, surgery,

Front 54

What is the MOA and Use of Aspirin?

Back 54

MOA: Irreversible cyclooxygenase (COX1) inhibitor and inhibits the fomation of thromboxane A2 (TXA2)

Clinical Use: Prevention of atherosclerosis, thrombosis, transient ischemic attacks; unstable angina

Platelets only have COX1
-it is irreversible and binds to COX make it inactive
-Platelets has a t1/2 of 7 days, so if you block COX you can’t aggregate/make anymore
-Endothelium has COX1 and COX2

Front 55

How does Dabigatran affect platelet aggregation?

Back 55

Prevent GPIIb-IIIa receptors

Daigatran blocks thrombin (IIa)
-It indirectly affects the linkage of fibrinogen
-Now you can’t have a red clot, just a white one

Front 56

What are the ADRs and Contraindications of Aspirin?

Back 56

ADR:
1.Bleeding and thrombocypenia
2.Gastrointestinal irritation
3.Aspirin Induced Asthma (hypersensitivity reactions)

Contraindications:
Bleeding disorders, hypersensitivity and Reye’s syndrome

Front 57

What is the MOA and Use and ADR of Dipyridamole?

Back 57

Increases the formation of cAMP via PDE inhibition (weak antiplatelet drug) , coronary vasodilator (same as Milrone: PDE inhibitor)

Use:
Prosthetic heart valves; may be used as an adjunct with aspirin therapy

ADR:
GI distress, ANGINA, headache, dizziness and rash.

Front 58

What is the MOA, Use, ADRs, and Contraindications for Ticlopidine?

Back 58

MOA
Irreversible P2Y12 antagonist. Inhibits ADP-induced expression of platelet glycoprotein receptors and reduces fibrinogen binding and platelet aggregation

Use
Patients intolerant to aspirin; prevents thrombotic stroke.

ADRs
GI: nausea, vomiting and diarrhea
Bleeding; mild to moderate neutropenia, & FATAL AGRANULOCYTOSIS

Contraindications
Bleeding disorders, severe liver disease

Front 59

What is the MOA, Use, ADRs of Clopidogrel (Plavix)?

Back 59

Use
Prevention of atherosclerosis, thrombosis, transient ischemic attacks; unstable angina.

MOA
Similar to ticlopidine (IRREVERSIBLE P2Y12)
Inhibits the binding of ADP to its receptor which is involved in the activation of platelet glycoprotein receptors binding to fibrinogen.

ADRs
Bleeding, neutropenia and thrombocytopenia.

Front 60

What is the MOA, ADRs, DDI of Prasugrel?

Back 60

MOA
Irreversible antagonist of the P2Y12 receptor, which leads to prevention of GPII/IIIa complex formation

ADR:
CV, CNS, GI, neuromuscular, life-threatening allergic rxn

DDI:
NDS (alfalfa & bilberry)
NSAIDS
Warfarin

Front 61

What types of drugs are
Abciximab, Eptifibatide, Tirofiban?
What is their MOA?

Back 61

Antiplatelet drugs

-Glycoprotein IIb/IIIa inhibitors
Glycoproteins are receptors for fibrinogen and vW factor

-Platelet aggregation is mediated by fibrinogen crosslinking

Front 62

What is the MOA, Use, ADRs, Contraindications for Abciximab?

Back 62

Use
Percutaneous transluminal coronary angioplasty as adjunct with aspirin and heparin

MOA
Fab fragment that binds to platelet glycoprotein IIb/IIIa receptors and prevents binding to fibrinogen

ADRs
Bleeding, thrombocytopenia, hypotension and bradycardia

Contraindications
Aneurysm, bleeding, recent surgery, stroke

Front 63

What is the Use, MOA, ADRs for Eptifibate and Tirofiban?

Back 63

Eptifibate
USE:
Treat acute coronary syndrome and for angioplastic coronary intervention
Given in conjunction to heparin and aspirin

MOA:
CYCLIC PEPTIDE inhibitor of IIb/IIIa binding site
ADRs:
Bleeding & thrombocytopenia

Tirofiban:
NON-PEPTIDE small molecule that inhibits IIb/IIIa binding site