Anti coagulants and anti platelets

Question 1

what is thormbosis

Answer 1

Is the formation of unwanted clot within a blood vessel.

Question 2

what does thrombus formation depend on?

Answer 2

depends largely on platelet activation, which causes
activation of coagulation cascade

Question 3

what is a thrombus

Answer 3

Fibrin-platelet network traps RBCs & WBCs, forming a viscous mixture which is attached to the vessel wall

Question 4

what is an embolus

Answer 4

thrombus detaches from vessel wall and floats within blood

Question 5

what is a hemostatic plug

Answer 5

thrombus formation occurs due to a cut or puncture in a blood vessel, it is beneficial because it stops bleeding.

Question 6

what causes the different types of thrombosis

Answer 6

Arterial thrombosis is caused by atherosclerosis, which involves endothelial erosion.

Venous thrombosis is caused by blood stasis
or inappropriate activation of coagulation cascade they are rich in fibrin, with fewer platelets than are
observed with arterial clots. Numbness of various body parts.

Question 7

what are the two functions of endothelial cells

Answer 7

A) isolating platelets from collagen, which
has a high affinity for platelets.

B) secreting prostacyclin, NO and adenosine

Question 8

what does prostacyclin, NO, and adenosine do

Answer 8

prostacyclin binds to prostacyclin receptors, causing accumulation
of cAMP, which inhibits secretion of granule
contents from platelets.

NO is also released from endothelium &
inhibits platelet activation.

adenosine in plasma activates
platelet adenosine A2 receptors——increases cAMP.

Question 9

what happens after you get injured

Answer 9

platelet activation which involves:

• adhesion of platelets to the site of injury (due to the exposure to subendothelial collafen)
• degranulation of granules stored in platelets ( which means the granules will relases their contacts such as PAF, serotonin, thrombin, thromboxane A2)
• platelet aggregation.

Question 10

what will the factors do after getting released

Answer 10

bind to receptors on other circulating platelets & activate them by causing Ca2+ release, which causes:
1) Degranulation.
2) Release of Arachidonic Acid (AA) from platelet membrane.
3) Activation of fibrinogen receptors (glycoprotein IIb/IIIa) on platelet outer membrane these receptors bind to fibrinogen, which bridges between 2 platelets
4) a meshwork develops

Question 11

what does arachidonic acid do

Answer 11

AA is converted to thromboxane A2 by cyclooxygenase (COX).
Resultant granule contents & TXA2 are released from the platelet, recruit surrounding platelets and activate them.

Question 12

what does arachidonic acid do

Answer 12

AA is converted to thromboxane A2 by cyclooxygenase (COX).
Resultant granule contents & TXA2 are released from the platelet, recruit surrounding platelets and activate them.

Question 13

• Platelet activators:
activate aggregation &
release of granules.
• Platelet inhibitors:
inhibit aggregation &
release of granules.

Question 14

At the same time, injury of endothelial cells causes exposure of
tissue factor (TF), which activates clotting factor VII, thus
initiating a series of proteolytic activation of other clotting
factors, which finally leads to proteolysis of prothrombin into
thrombin

Question 14

At the same time, injury of endothelial cells causes exposure of
tissue factor (TF), which activates clotting factor VII, thus
initiating a series of proteolytic activation of other clotting
factors, which finally leads to proteolysis of prothrombin into
thrombin

Question 15

what does thrombin do

Answer 15

 Proteolyses fibrinogen into fibrin.

 Activates another clotting factor which, in turn, cross-links fibrin, thus making fibrin insoluble.

 Activates clotting factors upstream in the cascade→ ↑
thrombin.

 Activates platelets.
• Fibrin-platelet network traps RBCs & WBCs → a clot.

Question 16

what is plasminogen

Answer 16

plasminogen activators from tissues activate
plasminogen into plasmin (fibrinolysin), which dissolves the fibrin network while the wound heals

Question 17

about aspirin (anti platlete) answer the following
MOA
S/E
INDICATION

Answer 17

MOA
inhibits COX1 irreversibly.—– inhibits conversion of AA into TXA2

S/E
- Hemorrhagic stroke, GIT bleeding.
• Risk-versus-benefit measure of aspirin as OTC prophylactic drug is
questionable for patients with PUD.

INDICATIONS
-prophylactic in transient cerebral ischemia (TCA).
- to prevent ischemic stroke.
-in angina.
-to reduce recurrence of MI

notes
Recommended daily dose: 81 mg.

Higher doses inhibit prostacyclin synthesis.

(NSAIDs) other than aspirin
inhibit COX1 by transiently binding at the catalytic site less persistent antiplatelet effect.

Question 18

about Ticlopidine, Clopidogrel, Prasugrel, and Ticagrelor (antiplate)
answer the following
MOA
INDICATION

Answer 18

MOA: block ADP receptors on platelet

Indications:
-prevent vascular events in patients with transient ischemic attacks
(TIA), except for prasugrel, which is contraindicated in patients with
history of TIA or stroke.
-prevent thrombotic stroke.
-unstable angina. -Following MI
-to prevent thrombosis in patients undergoing
percutaneous coronary intervention (PCI)
w or w/out placement of a coronary stent.
- To prevent thrombosis in patients who
received a stent.
Useful in patients who cannot tolerate aspirin or who failed aspirin.

Question 19

what are - Ticlopidine side effects

Answer 19

• Hemorrhage
• Neutropenia.
• Thrombotic thrombocytopenic purpura (TTP) 
disseminated مبعثرة platelet-rich small thrombi, platelet
consumption, thrombocytopenia, & increased bleeding tendency.
• Aplastic anemia.
 should monitor WBCs and CBC during the first 3 months.
Ticlopidine should be reserved for cases intolerant to other agents

Question 20

what are Clopidogrel S/E

Answer 20

No need for CBC monitoring
• Neutropenia.
• TTP.
• Clopidogrel has a black box warning for patients who are poor
metabolizers, since it is a prodrug, and its therapeutic effect relies
entirely upon its active metabolites.
• Tests are currently available to identify poor metabolizers

Question 21

what are the S/E for Prasugrel and ticagrelor

Answer 21

Carry black box warning for bleeding, for which there is no antidote and can be fatal.

• Ticagrelor: black box warning for diminished effectiveness with
concomitant use of aspirin doses above 100 mg.

Question 22

answer the following about Dipyridamole & Cilostazol:
MOA

Answer 22

1. inhibits phosphodiesterase 3 ↑ cAMP potentiates effects of prostacyclin platelet inhibition.
   Also, inhibition of PDE3 ↑ cGMP vasodilation.
2. Inhibit the uptake of adenosine by endothelial cells and erythrocytes ↑ plasma concentration of adenosine.
   Adenosine acts through platelet adenosine A2 receptors
   ↑ platelet cAMP  inhibit aggregation.

Question 23

what are Dipyridamole indications and S/E

Answer 23

indications
-with aspirin for prophylaxis in angina and secondary prevention of
ischemic stroke.
-with warfarin to inhibit embolization from prosthetic heart valves/
more effective than with aspirin

S/E
-Dipyridamole can cause orthostasis in the elderly. Also:
palpitations.

Question 24

what are cilostazol indications and S/E

Answer 24

indications

• Also has vasodilating effect.
• For intermittent claudication that results from peripheral arterial
  disease due to blood vasoconstriction.
• For chronic cerebral ischemia

S/E
- Headache & GI A/Es (diarrhea, abdominal pain….).
- C/I in patients with HF of any severity (-ve inotropic effect).
- Palpitations

Question 25

what are the systems that oppose clot formation

Answer 25

• Fibrin inhibition:
Plasma contains protease inhibitors like Antithrombin III (ATIII),
protein C, and S that rapidly inactivate coagulation proteins as they
escape from site of vessel injury.

• Fibrinolysis:
Injured cells release activators of plasminogen plasmin.
• Plasmin achieves fibrinolysis limits extension of thrombosis.

Question 26

what is heparin
10+2

Answer 26

rin
• Its is a thrombin II inhibitor and X and other factors inhibitor.
• aka unfractionated heparin (UFH)
• Commercial heparin is extracted from porcine intestinal mucosa
& bovine lung.
• A heterogeneous mixture of anionic sulfated
mucopolysaccharides with a wide range of molecular weights.
• Eliminated by lungs, RES of liver, & kidney longer t1/2 in hepatic or renal disease.

Question 27

what is UFH MOA (heparin) 10+2

Answer 27

• Prevents further thrombus growth, allowing the body’s own
thrombolytic system to dissolve clot.
• Activates plasma protease inhibitor antithrombin III (AT III).
• The complex inactivates factors:
XIIa, XIa, IXa, Xa, & IIa (thrombin) inhibits fibrin formation.

Question 28

what are heparin indications 10+2

Answer 28

-Prevent thrombus expansion in deep vein thrombosis (DVT) &
pulmonary embolism.
-Prevent postoperative venous thrombosis in patients undergoing
surgery, for example hip replacement.
-MI to prevent thrombosis resulting from thrombolytic use.
-In extracorporial devices (like dialysis machines) to prevent
thrombosis.
-Prosthetic heart valves (esp. in pregnant women because it does
not cross placenta-large & charged).
-In combination with glycoprotein IIb/IIIa inhibitors during angioplasty and placement of coronary stents.

Question 29

how do we dose and administer heparin 10+2

Answer 29

UFH can also be administered as intermittent IV injections BID.
•
Can be given in deep SQ tissue for prophylaxis.
•
IM route is not used due to risk of hematoma (a localized
collection of blood, usually clotted, in a space or tissue).
•
Duration: For DVT & PE, heparin is given for 7-10 days.
•
Effect of heparin is not predictable because it binds to many plasma
proteins that neutralize its activity, and this binding is variable
between patients.

Question 30

what monitoring do we need to do for heparin 10+2

Answer 30

• Activated partial thromboplastin time (aPTT):
• Normal aPTT is 24-36 sec.
• An aPTT ratio (patient aPTT/control aPTT) of 1.5–2.5 should
be achieved throughout infusion or 6 hours after intermittent
administration.

Question 31

what are the heparins S/E 10+2

Answer 31

1. The major adverse effect is bleeding : even with therapeutic aPTT
   (due to effect on platelets & vascular permeability).
   •
   Among symptoms of bleeding with heparin therapy: sever
   headache, joint, chest & / or abdominal pain.
   •
   Can cause hemorrhagic stroke.
    Infuse protamine sulfate slowly. Protamine is rich with arginine
   positive charges. (protamine is a weak anticoagulant agent)
   (Very important to titrate the dose of protamine carefully)
2. Hypersensitivity: heparin is of animal origin chills, fever, urticaria,
   & anaphylactic shock.
3. Thrombosis !: with long-term or intermittent use of heparin
   reduction of ATIII activity limit to a low dose.
4. Increased loss of hair (reversible alopecia)
5. Long-term heparin therapy: osteoporosis
6. Hyperkalemia (decreases aldosterone)
7. Heparin-induced thrombocytopenia (HIT): a hypercoagulable state
   of severe thrombocytopenia and thrombosis due to formation of
   antibodies against a complex of heparin and platelet factor 4.
   Thrombocytopenia is common with heparin, but the drug should be D/C
   if it is severe, & use others: dabigatran, lepirudin, or argatroban.
   • HIT can cause severe thrombotic complications in arteries and veins
   (i.e. limb artery occlusion , stroke , MI , DVT , PE ) and skin lesion
   that may involve dermal necrosis , requiring amputation.

Question 32

what are heparin’s contraindications 10+2

Answer 32

-bleeding disorder.
-hypersensitivity to heparin.
-having or having had a recent surgery in the brain, spinal cord, or eye.
Alcoholic patients.

Question 33

what is low molecular weight heparins (LMWHs) 10>2

Answer 33

Enoxaparin, dalteparin, tenzaparin & ardeparin are
fragments of heparin.
• Generally better than heparin replacing it.
• as opposed to heparin, their complex with ATIII preferentially
inactivates factor Xa & minimally affects thrombin.
• products vary in the ratio of their activity against thrombin & factor
Xa can’t be used interchangeably.
• Since LMWHs minimally affect thrombin, they have minimal impact
on the aPTT (which is most sensitive to thrombin).
• Peak anticoagulation effect of LMWHs is seen after 3 – 5 hours of
subcutaneous injection .

Question 34

what is enoxaparin 10>2

Answer 34

from same sources as regular heparin.
• Eliminated renally.
• Higher costs for these agents may be outweighed by earlier discharge
from hospital due to dosing convenience.
• Neutralization by protamine is incomplete.
• Indications of LMWHs are similar to those of heparin.

Question 35

what are the advantages of LMWHs 10>2

Answer 35

• ↓ laboratory monitoring:
Blood conc determined only in renal failure, pregnancy, & obesity
• Less binding to plasma proteins
• ↑ predictability of response
• Longer t1/2 once-twice daily injections
• Ease of dosing & administration (SQ)
• ↓ requirement of hospitalization
• ↓ risk of thrombocytopenia
• ↓ risk of osteoporisis.
• Less thromboembolic problems.
• More bioavailability as SQ injection

Question 35

what are the advantages of LMWHs 10>2

Answer 35

• ↓ laboratory monitoring:
Blood conc determined only in renal failure, pregnancy, & obesity
• Less binding to plasma proteins
• ↑ predictability of response
• Longer t1/2 once-twice daily injections
• Ease of dosing & administration (SQ)
• ↓ requirement of hospitalization
• ↓ risk of thrombocytopenia
• ↓ risk of osteoporisis.
• Less thromboembolic problems.
• More bioavailability as SQ injection

Question 35

what are the advantages of LMWHs
10>2

Answer 35

• ↓ laboratory monitoring:
Blood conc determined only in renal failure, pregnancy, & obesity
• Less binding to plasma proteins
• ↑ predictability of response
• Longer t1/2 once-twice daily injections
• Ease of dosing & administration (SQ)
• ↓ requirement of hospitalization
• ↓ risk of thrombocytopenia
• ↓ risk of osteoporisis.
• Less thromboembolic problems.
• More bioavailability as SQ injection

Question 36

what are the side effects of LMWH 10>2

Answer 36

• Bleeding.
• Reactions at the injection site: irritation, pain,
hematoma, bruising & redness
• HIT: platelets should be measured at baseline &
between days 3 and 5 of therapy.

Question 37

what is Fondaparinux 10

Answer 37

A synthetic drug that contains the active pentasacharide present in
UFH & LMWHs no variability in biological activity.
It is a specific Xa inhibitor.
- Binds to ATIII inactivates Xa.
-SQ, once daily
Indications:
-Can be given in place of LMWH
-For prophylaxis of DVT in patients undergoing orthopedic
surgery.
- With warfarin for acute pulmonary embolism or acute DVT.
- Patients with HIT (to replace UFH or LMWH).
- Requires less monitoring than heparin.
- C/I in patients with severe renal failure.
- A/E: bleeding.

Question 38

what are rivaroxaban and apixaban 10

Answer 38

Direct Oral Factor Xa inhibitors
- Have a rapid onset of action and shorter half-lives than warfarin.
- Given as fixed ORAL doses and do not require monitoring.
- Adverse effects: bleeding. No reversal agents exist.

Question 39

what are Hirudin (a protein derived from leech saliva), lepirudin, bivalirudin, desirudin, argatroban, melagatran.

Answer 39

Direct & specific thrombin inhibitors
Lepirudin is the recombinant form of the leech protein hirudin.
• Action is independent of AT III → can reach & inactivate fibrin-bound
thrombin in thrombi.
Given parenterally.
Do not bind platelet factor 4Have little effect on platelets or the
bleeding time.
Indicated in HIT or those at risk to have HIT, & in percutaneous
coronary angioplasty (PCI).
• Monitored by the aPTT.
• A/E: bleeding, for which there is no antidote.
• Argatroban is metabolized in the liver can be used in renal
dysfunction but with caution in hepatic dysfunction.

Question 40

what is dabigatran exexilate

Answer 40

A prodrug for the active moiety: dabigatran.
- Dabigatran is a direct thrombin inhibitor.
- Dabigatran is the first ORAL anticoagulant in 50 years to be approved
after discovery of warfarin.
- Does not require frequent monitoring and has few drug interactions
compared with warfarin.
- A/E: bleeding.

Question 41

what is Warfarin 1972

Answer 41

• “Warfarin” from the Wisconsin Alumni Research Foundation.
• Was initially used as a rodenticide.
• Generally used as sodium salt & has 100% bioavailability (it’s not
affected by food).
• > 99% is bound to plasma albumin → long half life.

MOA

• Blocks carboxylation of clotting factors VII, IX, & X, & II as well as
the proteins C and S.
• The blockade results in incomplete clotting
factors with weak coagulation activity.
• This carboxylation is physiologically
coupled with the oxidative deactivation
of vitamin K.
• Warfarin prevents reductive metabolism of
inactive vitamin K epoxide back to vitamin K

indications

• Deep vein thrombosis & pulmonary embolism : to prevent
recurrence or progression used after initiating heparin
therapy.
• During orthopedic or gynecologic surgery: to prevent
thrombosis.
• Prophylactic in patients with acute MI, prosthetic heart valve,
& chronic atrial fibrillation.
• In general, warfarin is used for chronic anticoagulation in all of
the clinical situations described previously for heparin, except
in pregnant women

ADMINISTRATION
• Initiation is recommended at a dose of 5 mg daily.
• Prothrombin time (Normal PT is 12 sec).
• International normalized ratio (INR) is the prothrombin
time ratio (test/control) obtained if reference tissue factor
made from human brain is used rather than rabbit brain).
• For DVT, the goal INR range is 2.0 to 3.0, with a target
goal of 2.5.
• Bleeding still occurs with INR = 2-3.
• Initial adjustment of warfarin dose takes ~ 1 week
• The effect of a small dose change with warfarin may not be seen
for 5 - 7 days.
• Action starts ~12 hrs after oral administration.
• Full therapeutic effect is not achieved until existing factor II is
cleared 72-96 hours.
• heparin or enoxaparin must be overlapped with warfarin &
continued for 4–5 days until an INR between 2.0 and 3.0 is
reached.
• Long term warfarin therapy ( >1 year ) is indicated in some
states, like recurrent VTE (venous thrombo-embolism).
Otherwise , treatment duration is 1.5 – 6 months.

Question 42

what are warfarin’s interactions and toxicity 1972

Answer 42

1. Pharmacokinetic mechanisms
   • enzyme induction,
   • enzyme inhibition,
   • ↓ plasma protein binding.
2. Pharmacodynamic mechanisms
   • synergism (impaired hemostasis),
   • competitive antagonism (vitamin K).
   • The use of a drug that interacts with warfarin is not absolute
   contraindication to addition of warfarin.

Narrow TI.
1.
Bleeding – the most dangerous, esp. intracranial hemorrhage.
2. Pregnancy: warfarin crosses the placenta readily & can cause
hemorrhagic disorders & abnormal bone formation in the fetus.
Thus, warfarin should never be administered during pregnancy
(FDA pregnancy category X).
3. Early in therapy, a period of hypercoagulability with subsequent
dermal vascular necrosis can occur. This is due to deficiency of
protein C.
4. Purple toe syndrome (cholesterol emboli from plaques → arterial
obstruction).

Question 43

what are warfarin’s interactions and toxicity

Answer 43

1. Pharmacokinetic mechanisms
   • enzyme induction,
   • enzyme inhibition,
   • ↓ plasma protein binding.
2. Pharmacodynamic mechanisms
   • synergism (impaired hemostasis),
   • competitive antagonism (vitamin K).
   • The use of a drug that interacts with warfarin is not absolute
   contraindication to addition of warfarin.

Narrow TI.
1.
Bleeding – the most dangerous, esp. intracranial hemorrhage.
2. Pregnancy: warfarin crosses the placenta readily & can cause
hemorrhagic disorders & abnormal bone formation in the fetus.
Thus, warfarin should never be administered during pregnancy
(FDA pregnancy category X).
3. Early in therapy, a period of hypercoagulability with subsequent
dermal vascular necrosis can occur. This is due to deficiency of
protein C.
4. Purple toe syndrome (cholesterol emboli from plaques → arterial
obstruction).

Question 44

how do we treat a warfarin over dose 1972

Answer 44

• Withdraw warfarin
• Oral vitamin K1
In more serious bleeding:
• Vitamin K1
(phytonadione) IV (diluted & given slowly to avoid
hypotension).
• Effect of vitamin K develops after ~ 24 hours.
• In case of major bleeding - fresh frozen plasma or factor
concentrates (prothrombin). (Contains the clotting factors)

Question 44

how do we treat a warfarin over dose 1972

Answer 44

• Withdraw warfarin
• Oral vitamin K1
In more serious bleeding:
• Vitamin K1
(phytonadione) IV (diluted & given slowly to avoid
hypotension).
• Effect of vitamin K develops after ~ 24 hours.
• In case of major bleeding - fresh frozen plasma or factor
concentrates (prothrombin). (Contains the clotting factors)

Question 45

what are warfarins contraindications 1972

Answer 45

Absolute:
• pregnancy
-bleeding disorder.
-hypersensitivity
-having or having had a recent surgery in brain, spinal cord, or eye.
Alcoholic patients
Relative:
• severe hepatic or renal disease
• vitamin K deficiency
• chronic alcoholism
• NSAIDs therapy

Question 46

what are thrombolytics

Answer 46

Streptokinase, anistreplase, alteplase, tissue plasminogen activator,
tenecteplase, reteplase, & urokinase.
Both protective hemostatic thrombi & target pathogenic
thromboemboli are broken down.
Circulating fibrinogen will also be degraded
Bleeding can occur.
However, these drugs differ in their selectivity to plasminogen in
clots & circulating plasminogen.

Question 46

what are thrombolytics

Answer 46

Streptokinase, anistreplase, alteplase, tissue plasminogen activator,
tenecteplase, reteplase, & urokinase.
Both protective hemostatic thrombi & target pathogenic
thromboemboli are broken down.
Circulating fibrinogen will also be degraded
Bleeding can occur.
However, these drugs differ in their selectivity to plasminogen in
clots & circulating plasminogen.

Question 47

what are the indications for thrombolytics

Answer 47

• Indications:
• Used less than before.
• IV for:
-Multiple pulmonary emboli
-Central deep venous thrombosis (eg, superior vena caval
syndrome, ascending thrombophlebitis of iliofemoral vein).
-Acute myocardial infarction:
• Greatest benefit for thrombolytic therapy is achieved when it is
given early, within 6 hrs after onset of acute MI.
-Acute ischemic stroke: tPA should be used within 3 hours after
onset of symptoms.
- Thrombolytics are reserved for patients in whom angioplasty is not
an option or until the patient can be taken to a facility where
angioplasty can be performed.
- To restore catheter and shunt function.
- Intra-arterially for: -Peripheral vascular disease

Question 48

what are streptokinase and anistreplase

Answer 48

MOA
Combines with plasminogen. The
complex cleaves another plasminogen
molecule to plasmin

indirect acting

from streptococcus

IV or IA

nonselective (both in clot and circulation fibrinogen)

antigenic and causes hypersensitivity

effects hemostatic plug

cant be used in pregnancy

Aminocaproic acid is the antidote

Question 49

what are urokinase, tPA, Alteplase

Answer 49

MOA
cleaves plasminogen to plasmin

direct acting

urokinase——from human urine
t-PA——from endothelium
Alteplase—– recombinant T-PA

IV andIA

affect the fibrin in the clot only (selective)

Doesn’t affect the hemostatic plug

contraindicated in pregnancy

aminocaproic acid is the antidote