Slides PharmacologyOfBloodCoagulation

Coagulation
With Dr. PJ Shukle
andy ramos ramos, jhody.jaro1@gmail.com

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General Principles
You do not need to know brand names for exams.

• Brand names are useful in real practice.
• Brand names change with time, and with regions of the world.

Pharmacology of Coagulation
COX inhibitors: Aspirin

Antiplatelets Glycoprotein IIb/IIIa inhibitors
ADP inhibitors: clopidogrel
PDE inhibitors
Anticlotting
drugs tPA derivatives
Thrombolytics Streptokinase
Heparins
Drugs used Anticoagulant Direct thrombin Inhibitors
in clotting Drugs Warfarin
Direct factor Xa inhibitors
Replacement factors
Drugs that
Vitamin K
facilitate Antiplasm drugs
clotting Vasopressin agonists
Monoclonal antibodies

Translocation Tethering of
Antiplatelets: Looking at a platelet aIIbb3 platelets
a granule
a2b1
Adhesion GPIb/IX/V Dense granule
• GPIIb/IIIa (called αIIbβ3 in Europe) allow Collagen

vWF Primary adhesion
and activation
Aggregation GPVI
aIIbb3
a2b1
• GPIIb/IIIa (called αIIbβ3 in Europe) cross-
links other platelets as well as binds to
vWF. Fibrinogen Aggregation
Release
• Thromboxane A2 and ADP is released ADP Thromboxane

when platelets bind to damaged tissue. A2

Antiplatelets: Aspirin
• Irreversible inhibition of Cyclooxygenase
• Used to manufacture thromboxane A2
• Platelets are permanently inhibited.
• Replacement platelets restore overall

function in 3 7 days.
Interactions:
• NSAIDs may also impair platelet
aggregation for a few hours.

Antiplatelets: Glycoprotein IIb/IIIa Inhibitors
Primary adhesion
and activation
GPVI
Reversibly inhibits GPIIb/IIIa aIIbb3
a2b1
• Reduced adhesion
• Reduced aggregation Fibrinogen Aggregation
Eptifibatide, tirofiban
ADP Thromboxane
A2

Antiplatelets: ADP inhibitors
Inhibition of the ADP receptor Translocation Tethering of platelets
aIIbb3
• Inhibit ADP-mediated aggregation a granule
a2b1
GPIb/IX/V Dense granule
Clopidogrel (PlavixR), prasugrel (EffientR), Collagen

vWF
ticlopidine (TiclidR) Primary adhesion
and activation
• Requires hepatic conversion to be active.
GPVI
aIIbb3
a2b1
• Irreversible inhibition
Fibrinogen
Aggregation
Ticagrelor (BrilantaR, BriliqueR, PossiaR)
• Does not require hepatic activation.

ADP Thromboxane
• Reversible inhibition of ADP receptor A2

Antiplatelets: PDE/Adenosine Uptake Inhibitors
These agents (dipyridamole, cilostazol) have a dual mechanism:
1. Inhibit phosphodiesterase to reduce cAMP degradation

• cAMP is an inhibitor of platelet aggregation.
• More cAMP means less platelet aggregation.
2. Inhibit uptake of adenosine

• increases plasma concentration of adenosine
• Adenosine acts through the A2 inhibitor on the platelet surface.
• A2 receptor activation causes increase in platelet cAMP levels.
• Less platelet aggregation

Antiplatelets: Uses
Aspirin Reduce subsequent MI, stroke, peripheral arterial ischemia
Eptifibatide, Prevent restenosis after angioplasty, used in ACS

tirofiban
Clopidogrel
Dipyridamole Adjunct to warfarin in patients with heart valve replacement
Adjunct to aspirin in patients for secondary prevention of stroke
Cilostazol Treat intermittent claudication

Antiplatelets: Toxicity
Aspirin Bleeding (0.3 %)
Ticlopidine Bleeding (5 %), severe neutropenia (1 %), TTP (rare)
Eptifibatide, Bleeding, thrombocytopenia (chronic use)

tirofiban
Clopidogrel Bleeding (< 1 %)
Dipyridamole Bleeding (1 2 %)
Cilostazol Contraindicated in heart failure

Anticoagulants: Heparins and Fondaparinux
Unfractionated Heparin
• Unfractionated heparin has a wide variety of

molecules in mixture (3,000 25,000 Da).
• Highly acidic; neutralized by a base

(i.e. protamine)
• Binds to antithrombin III to form a complex

• Inactivates thrombin and Xa
(and others)

Unfractionated Heparin
• Always given IV or SC; do not give IM.
• May cause a moderate, transient

thrombocytopenia.
• HITT: heparin induced
thrombocytopenia and thrombosis
• May be linked to osteoporosis

in chronic use.

Low molecular weight heparins (LMWH)
• Do not bind to thrombin but inactivate Xa
• aPTT is therefore not reliable
• Use Factor Xa levels if you need

monitoring
• Far more predictable than UFH
• Given as once- or twice- daily SC injections
• Enoxaparin (LovenoxR), dalteparin

(FragminR), tinzaparin (InnohepR)

Fondaparinux (ArixtraR)
• Synthetic drug, pentasaccharide found in

LMWH
• (Probably) the active site on heparin

molecules to bind ATIII
• Increases the anticoagulant effects

of ATIII 1000x!
• Does not inhibit thrombin
• Daily subcutaneous dose

Anticoagulants: Direct Thrombin Inhibitors
• Derived from the medicinal leech

Hirudo medicinalis
• Bind to thrombin and thrombin

substrates
• Bind to thrombin in the serum AND

in clots (unlike heparin)
• Often used as an alternative in

patients who had HITT
H. Krisp, https://upload.wikimedia.org/wikipedia/commons/thumb/a/a4/Hirudo_medicinalis.jpg/800px-Hirudo_medicinalis.jpg CC BY 3.0

• Can use the aPTT to evaluate

efficacy
• Bivalirudin
• Argatroban short-acting (4 hours)

• Binds to thrombin active site
only
H. Krisp, https://upload.wikimedia.org/wikipedia/commons/thumb/a/a4/Hirudo_medicinalis.jpg/800px-Hirudo_medicinalis.jpg CC BY 3.0

Dabigatran (PradaxaR)
• Twice daily oral medication
• Approved for stroke prevention in atrial fibrillation
• Also used in DVT prevention in post-op hip and knee

surgery
• Antidote idarucizumab (PraxbindR) was approved for

use in march 2016.

Anticoagulants: Warfarin
Warfarin (CoumadinR)
• Acenocoumarol (Latin America),

phenprocoumon (EU)
• Small, lipophilic molecules interfere with

vitamin K dependent factors.
• Inhibits vitamin K epoxide reductase (VKOR)
• Factors II, VII, IX, and X
• Inhibitory factors C and S

• Inhibition starts with the inhibitory
Relative factor concentration

factors C and S. This gives a
procoagulant effect. 1.0
II
0.8 VII
• After 1 day, factor IX is affected. IX
X
0.6 C
Net effect S
0.4
• Initial period of hypercoagulability,
followed by hypocoagulability
0.2
0 2 4 6 8 10
• This is why we
Time after warfarin start (days)
patient with heparin when we start
or stop warfarin.


Interactions: non-pharmacological
1.0
• Normal gut flora helps us make II
vitamin K. 0.8 VII
IX
X
• Antibiotics may kill off normal 0.6 C
gut flora. S
0.4
• You become vitamin K deficient.
• 3 7 days after starting a broad 0.2

0 2 4 6 8 10
climb.


1.0
Interactions: pharmacological II
0.8 VII
• CYP450 inducers (carbamazepine, IX
X
phenytoin, barbiturates, rifampin) 0.6 C
increase clearance and drop INR. S
0.4
•
cimetidine) reduce clearance and 0.2
increase the INR. 0 2 4 6 8 10


Warfarin toxicity
1.0
• The most specific antidote for II
warfarin toxicity is vitamin K. 0.8 VII
IX
X
• Vitamin K takes several hours to 0.6 C
reverse the effects of warfarin. S
0.4
• In case of life-threatening
hemorrhage, additional measures
0.2
need to be taken, e.g. 0 2 4 6 8 10
administration of fresh frozen Time after warfarin start (days)
plasma or prothrombin complex
concentrate.

Factor Xa Inhibitors
• Directly bind to Xa
• Rivaroxaban, apixaban
• Approved for use in stroke prevention in non-valvular atrial fibrillation
• Also used in post-op hip and knee surgeries for DVTP
• May soon be used in aspirin replacement (COMPASS study)
• No reversal agent

Thrombolytics
Plasminogen
• Catalyze conversion of
plasminogen to plasmin Fibrinolytics Antiplasmin drugs
tPA analogs +
(e.g. alteplase) Aminocaproic acid,
• Plasmin breaks down fibrin.
tranexamic acid
• Used in acute stroke (after CT Streptokinase +
+
confirms no hemorrhage!) Plasminogen
Plasmin
• Was used in acute MI; mostly
replaced by PCI + +
Thrombin
Degradation Fibrinogen Fibrin Fibrin split
Adverse events products products
• Bleeding, intracerebral
hemorrhage

Thrombolytics
Plasminogen
Fibrinolytics Antiplasmin drugs

tPA analogs +
Streptokinase
tranexamic acid
• Does not show affinity for fibrin-bound Streptokinase +
plasminogen +
Plasminogen
tPA analogues Plasmin
• Show affinity for fibrin bound + +

plasminogen Thrombin
Degradation Fibrinogen Fibrin Fibrin split
• Alteplase: normal human tPA products products

Thrombolytics
Plasminogen
Fibrinolytics Antiplasmin drugs

tPA analogs +
Streptokinase
tranexamic acid
• Does not show affinity for fibrin-bound Streptokinase +
plasminogen +
Plasminogen
tPA analogues Plasmin
• Tenecteplase: +
mutated human tPA Thrombin
longer duration of action Degradation Fibrinogen Fibrin Fibrin split
products products
• Reteplase:
mutated human tPA
faster onset, longer duration

Procoagulants Vitamin K (Phytonadione)
• Fat soluble vitamin (along with A, D, and E)
• Note: oral dosing may be faster than IV dosing

Procoagulants Replacement Factors
• Fresh plasma
• Purified human clotting factors

• Factor VIII concentrate (for hemophilia A)
• Factor IX concentrate (for hemophilia B)
• OctaplexR and BeriplexR: mixture of factors II, VII, IX, X, C,

used in mixed deficiencies, and NOAC overdose
• Monoclonal antibody
• Idarucizumab (PraxbindR): approved in March 2016

Procoagulants Vasopressin Agonists
• Desmopressin is a V2 agonist
• Increases the concentration of vWF and factor VIII
• Used to prepare hemophilia A or vWD patients for surgery

Procoagulants Antiplasmin Agents
• Aminocaproic acid (AmicarR) and tranexamic acid are oral agents.
• Inhibit fibrinolysis by inhibiting plasminogen activation
• Increases the concentration of vWF and factor VIII
Uses
• Treat hemophilia
• Prophylaxis for high risk patients
• Used in postoperative bleeding

Question 1: Pharmacology of Coagulation
The following medication will act upon thrombin in the serum and thrombin
enmeshed within clots:
A. Bivalirudin
B. Protamine
C. Fondaparinux
D. Enoxaparin
E. Unfractionated heparins

The following medication will act upon thrombin in the serum and thrombin
enmeshed within clots:
A. Bivalirudin
B. Protamine
C. Fondaparinux
D. Enoxaparin
E. Unfractionated heparins

Case Study 1: Pharmacology of Coagulation
A patient with a history of atrial fibrillation arrives in the ER with an acute GI
The spouse says the patient was not required to have monthly blood
monitoring. The pharmacy dispensed dabigatran in the last month.
What would the most appropriate antidote be?
A. Factor VII concentrate
B. Factor X concentrate
C. Factor IX concentrate
D. Octoplex
E. Idarucizumab

A. Factor VII concentrate
C. Factor IX concentrate
D. Octoplex
E. Idarucizumab

Dabigatran (Pradaxa) did

A. Factor VII concentrate not have an antidote until very recently. We used to
use octaplex or beriplex to treat dabigatran toxicity.
We use octaplex and biraplex to treat overdoses of the new target specific
factor
C. Xa inhibitors
Factor like rivaroxaban, and apixaban.
IX concentrate
More recently,
D. Octoplex a monoclonal antibody (idarucizumab) was developed that
antagonizes the activity of dabigatran. The reversal occurred within minutes.
E. idarucizumab
It is approximately $3500 per dose.

What is the mechanism of action of clopidogrel?
A. Blockage of an enzyme that produces Factor VIII
B. Cyclooxygenase inhibition
C. Binds to ADP receptors
D. Binds to cAMP receptors
E. Binds to GPIIb/IIIa receptors

A. Blockage of an enzyme that produces Factor VIII

A. Blockagebinds
Clopidogrel of anto
enzyme
the ADPthat produces
receptor on Factor VIII surface, preventing
the platelet
platelet recruitment and aggregation.
Cyclooxygenase is inhibited by aspirin
Factor VIII is reduced in certain types of hemophiliacs.
Direct GPIIb/IIIa inhibitors include eptifibatide and tirofiban.

This document is a property of: andy ramos ramos
Note: This document is copyright protected. It may not be copied, reproduced, used, or
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Coagulation

With Dr. PJ Shukle

andy ramos ramos, jhody.jaro1@gmail.com

You do not need to know brand names for exams.

andy ramos ramos, jhody.jaro1@gmail.com

COX inhibitors: Aspirin

andy ramos ramos, jhody.jaro1@gmail.com

• GPIIb/IIIa (called αIIbβ3 in Europe) allow Collagen

• Thromboxane A2 and ADP is released ADP Thromboxane

andy ramos ramos, jhody.jaro1@gmail.com

• Platelets are permanently inhibited.

• Replacement platelets restore overall

andy ramos ramos, jhody.jaro1@gmail.com

• Reduced aggregation Fibrinogen Aggregation

andy ramos ramos, jhody.jaro1@gmail.com

Clopidogrel (PlavixR), prasugrel (EffientR), Collagen

• Does not require hepatic activation.

andy ramos ramos, jhody.jaro1@gmail.com

1. Inhibit phosphodiesterase to reduce cAMP degradation

• More cAMP means less platelet aggregation.

2. Inhibit uptake of adenosine

• Adenosine acts through the A2 inhibitor on the platelet surface.

• A2 receptor activation causes increase in platelet cAMP levels.

• Less platelet aggregation

andy ramos ramos, jhody.jaro1@gmail.com

Aspirin Reduce subsequent MI, stroke, peripheral arterial ischemia

Eptifibatide, Prevent restenosis after angioplasty, used in ACS

Dipyridamole Adjunct to warfarin in patients with heart valve replacement

Adjunct to aspirin in patients for secondary prevention of stroke

Cilostazol Treat intermittent claudication

andy ramos ramos, jhody.jaro1@gmail.com

Aspirin Bleeding (0.3 %)

Ticlopidine Bleeding (5 %), severe neutropenia (1 %), TTP (rare)

Eptifibatide, Bleeding, thrombocytopenia (chronic use)

Clopidogrel Bleeding (< 1 %)

Cilostazol Contraindicated in heart failure

andy ramos ramos, jhody.jaro1@gmail.com

• Unfractionated heparin has a wide variety of

• Highly acidic; neutralized by a base

• Binds to antithrombin III to form a complex

andy ramos ramos, jhody.jaro1@gmail.com

• Always given IV or SC; do not give IM.

• May cause a moderate, transient

• May be linked to osteoporosis

andy ramos ramos, jhody.jaro1@gmail.com

• Do not bind to thrombin but inactivate Xa

• aPTT is therefore not reliable

• Use Factor Xa levels if you need

• Far more predictable than UFH

• Given as once- or twice- daily SC injections

• Enoxaparin (LovenoxR), dalteparin

andy ramos ramos, jhody.jaro1@gmail.com

• Synthetic drug, pentasaccharide found in

• (Probably) the active site on heparin

• Increases the anticoagulant effects

• Does not inhibit thrombin

• Daily subcutaneous dose

andy ramos ramos, jhody.jaro1@gmail.com

• Derived from the medicinal leech

• Bind to thrombin and thrombin

• Bind to thrombin in the serum AND

• Often used as an alternative in

H. Krisp, https://upload.wikimedia.org/wikipedia/commons/thumb/a/a4/Hirudo_medicinalis.jpg/800px-Hirudo_medicinalis.jpg CC BY 3.0

• Can use the aPTT to evaluate