Week 6: Drugs Affecting Coagulation & Hemophilias

What are titration labs?

labs that are used to find out if the dosing is right for an anticoagulation drug to meet therapeutic range

this is NOT the same as “what test can be done”, it is the CLINICAL CHOICE for the drug

What are anticoagulants?

drugs that PREVENT clot formation

What are parenteral drugs?

drugs given as SQ injections or IV

What are the 4 categories of parenteral drugs?

1. UFH

2. LMWHs

3. Fondaparinux

4. DTIs

What is UFH?

unfractionated heparin - a mixture of HETEROGENEOUS LONG glycosaminoglycan chains

What is the method of administration for UFH?

administered IV or sometimes as SQ injection

What is the MOA of UFH?

activates an inhibitor of coagulation → allosteric activation of ATIII and inhibitor of II_a and X_a

What is the specific sequence of UFH required for activation of ATIII?

the 5-saccharide sequence that BINDS to ATIII and ACTIVATES it

What is the specific sequences of UFH required for inhibition of factor II_a?

the 18-saccarhide sequence (long chain)

it is a sugar tail that snuggles up II_a and pushes it against ATIII to inhibit it

Is there a specific sequence required for X_a inhibition?

no; X_a is inhibited just by ATIII binding that 5-saccharide sequence

Which factor is inhibited most strongly: X_a or II_a?

they are inhibited equally

How rapid are the effects of UFH?

very rapid → it directly activates ATIII for inhibition of coagulation

What are the 2 titration labs that are used for UFH?

1. PTT

2. anti-X_a activity

Which pathway is inhibited by UFH?

COMMON pathway

• X_a is what activates II_a conversion

• II_a is what activates fibrin conversion and clot formation

How would we expect PT, PTT, and anti-X_a to be effected by UFH?

PT: increases (inhibiting common pathway)

PTT: increases (inhibiting common pathway)

Anti-X_a: increases (inhibiting X_a)

If we see titration lab levels increase, what does this mean?

this means the drug is WORKING to prevent clotting

What are the 2 AEs of UFH?

1. bleeding

2. heparin-induced thrombocytopenia (HIT)

Why do we get bleeding with any of these drugs as an AE?

the drugs are inhibiting coagulation (which is what typically stops bleeding)

What is HIT and what does this cause?

UFH triggers the body to make that attack platelets and increase the risk of clotting

mechanism: antibodies binds heparin & platelet factor 4 (PF4) located on platelets

this causes premature/inappropriate platelet activation, consumption, and thrombosis

Why does platelet count decrease with HIT?

HIT induces consumption of platelets → we are using them up due to premature activation and thrombosis (clot formation)

What are the two categories of drugs that are associated with HIT?

yes; cross reacts with UFH and LMWHs because they are similar in structure

What does cross reaction mean?

it means that if we take the drug that is similar to the one that caused the antibody formation in the first place → those antibodies previously made with cause HIT AGAIN

What is a reversal agent?

something that is able to reverse the effects of a drug

What is the name of the reversal agent for UFH?

PROTAMINE SULFATE

How does protamine sulfate work to reverse UFH-induced bleeding?

it binds the long heparin chains to prevent activation of ATIII → basically NEUTRALIZES heparin and is used to stop bleeding

Does protamine sulfate also work for HIT?

no; the only way to reverse HIT is to DISCONTINUE the drug and use something that will not interact with the antibodies (anything that is not UFH or LMWH)

What does the suffix -parin mean?

-parin = LMWH

What are the names of the 2 LMWHs? (low molecular weight heparins)

1. enoxaparin

2. dalteparin

What are LMWHs?

a HOMOGENOUS mixture of heparin with SHORTER chains

What is the method of administration of LMWHs?

SQ injection

What is the MOA of LMWHs?

*same as UFH

activates ATIII and inhibits X_a & II_a

Which factor is preferentially inhibited by LMWHs?

X_a » II_a

there is less inhibition of II_a because LMWHs have SHORTER chains (cannot snuggle up II_a to push against ATIII)

Which titration lab is used for LMWHs?

Anti-X_a activity

What do we expect PT, PTT, and Anti-X_a to be?

PT: increased

PTT: increased

Anti-X_a: detected

stopping coagulation by inhibiting common pathway and X_a

What are the 2 AEs associate with LMWHs?

1. bleeding

2. HIT

What are 2 possible reversal agents that are used to reverse LMWHs?

1. protamine sulfate

2. andexant alfa (off label)

Why does protamine sulfate not work as well for LMWHs than it does for UFH?

protamine sulfate prefers LONGER chains to inhibit ATIII → LMWHs have short chains

What is adexant alfa?

a decoy X_a molecule

it is a “fake” X_a molecule that basically keeps II_a busy and reverses the effects of LMWHs

What is Fondaparinux?

a 5-saccharide chain sequence

What is the route of administration of Fondaparinux?

SQ injection

What is the MOA of Fondaparinux?

*same as UFH

it is a 5 saccharide chain that activates ATIII and inhibits X_a

Why is there only X_a inhibition and not II_a?

this drug is only long enough to bind and activate ATIII (which is right next to X_a binding site)

not long enough to grab II_a

What is a fun way to remember what Fondaparinux does?

FondaPARINuX

F - five

PARIN - heparin type drug

X - factor X_a

Which titration lab is used for Fondaparinux?

anti-X_a activity

What do we expect PT, PTT, and Anti-X_a to look like?

PT: increased

PTT: increased

Anti-X_a: detected

inhibits common pathway

What is the AE of Fondaparinux?

bleeding

What is the reversal agent for this drug?

no reversal agent

Why can’t we use protamine sulfate?

it won’t work because there are no long chains to act on to neutralize the medication

What could possibly be tried off label as a reversal agent?

andexanet alfa → decoy X_a molecule

What do -rudin and -gat- mean?

parenteral DTIs

What are the names of the 2 parenteral DTIs?

1. Bivalirudin

2. Argatroban

What is the route of administration of DTIs? (direct thrombin inhibitors)

IV administration

What is the MOA of parenteral DTIs?

DIRECTLY inhibit II_a (thrombin)

Which titration lab is used for parenteral DTIs?

PTT

What do we expect PT, PTT, and anti-X_a to look like for these drugs?

PT: increased

PTT: increased

anti-X_a: normal

inhibit common path but not X_a

What is the AE of parenteral DTIs?

bleeding

What is the reversal agent for parenteral DTIs?

None

(not even adexenant alfa bc no X_a inhibition)

What are the names of the 5 parenteral anti-coagulant drugs?

1. UFH

2. LMWHs

3. Fondaparinux

4. Bivalirudin

5. Argatroban

What is the route of administration of Warfarin?

oral administration

What is the MOA of Warfarin?

inhibits hepatic vitamin K epoxide reductase (VKOR) which affects the SYNTHESIS of clotting factors

What is the importance of VKOR?

VKOR is an enzyme that reduces vitamin K

so by inhibiting VKOR, this prevents Vit K epoxide from being converted to reduced Vit K (reduced Vit K is needed for functional clotting factors to become functional)

If VKOR is inhibited, how does that impact clotting factors?

without VKOR, we have inhibited carboxylation of vitamin K dependent factors, making them nonfunctional

Describe how carboxylation helps activate clotting factors

clotting factors circulate as inactive in the blood and are only active at the site of injury when the platelet is activated → when Ca⁺⁺ binds the (-) phospholipids on the platelets and clotting factors, the carboyxlation is what allows them to WORK

Which are the 4 coagulation factors and the 2 anti-coagulation factors that are impacted by Warfarin?

coagulation: II (2), VII (7), IX (9), X (10)

anti-coagulant: C, S

they become DEPLETED over time based on their half lives

Which coagulation factor has the shortest half life?

VII (7) - 4-6 hours

has a large impact on INR

Which anti-coagulation factor has the shortest half life?

C

8 hours

Explain the mechanism of why the anti-coagulation medication warfarin does not work quickly

does not work quickly because you have to wait for all of the clotting factors to “drop off” or stop working → this depends on their half lives

to get the full effect of warfarin, they all have to use up their half lives

Why can patients have an increase in clotting initially when starting

warfarin?

because protein C (anti-coagulant) is vit k dependent → it is impacted by warfarin

factor C has short half life so if it drops out of circulation too fast or too soon → increased risk of clot formation → increased risk of coagulation (especially if the clotting factors have longer half lives)

Describe what happens inside the liver with carboxylation, VKOR, and Vit K

CFs (II, VII, IX, X) & AC (C,S) are inactive and nonfunctional → reduced VIT K + carboxylation causes them to be inactive but FUNCTIONAL (which is how they circulate around)

reduced Vit when used up becomes Vit K epoxide

VKOR converts Vit K epoxide to reduced Vit K → allowing it to aid in carboxylation and renders CF/AC as FUNCTIONAL

How does Warfarin impact this cycle?

Warfarin inhibits VKOR from converting Vit K epoxide to reduced Vit K → decreased Vit K = decreased carboxylation = nonfunctional CF/AC

What is the name of the enzyme that is responsible for Warfarin metabolism?

2C9 → CYP that breaks down warfarin to be inactive

Which titration lab is used for Warfarin?

PT/INR

What would we expect for PT, PTT, anti-X_a to look like?

PT: increased

PTT: increased

Anti-X_a : detected

blocking common pathway and intrinsic/extrinsic (blocks X_a formation)

What are the 3 AEs of Warfarin?

1. bleeding

2. initial period of increased risk of thrombosis

3. skin necrosis

Explain why there is an initial period of increased risk of thrombosis with Warfarin?

if protein C drops off too early (anti-coagulant) → can have increased thrombosis risk

What must be combined with Warfarin to prevent increased risk of thrombosis?

have to initially combine warfarin for 5 days with drugs that have RAPID anticoagulation properties

ex: UFH/LMWHs/fondaparinux

Why could skin necrosis be a possible AE of warfarin?

if we have thrombis in blood vessels in the skin → decreased blood flow in the skin and tissue can die

What are the 2 reversal agents that could be used for Warfarin?

1. vitamin k

2. kcentra

How does vitamin K work as a reversal agent?

it replenishes the pool of reduced vitamin K

What is another source of vitamin K in the body?

GI bacteria → makes vitamin K in the stomach

Why do people on Warfarin need a constant supply of vitamin K in their diet?

fluctuations in vitamin K could cause a FOOD-DRUG interaction that will impact the effectiveness of Warfarin and INR

In which 2 situations would we have decreased vitamin K?

1. if someone is not ingesting enough Vit K

2. if someone is taking antibiotics (kill GI bacteria)

How long does Vitamin K take to work properly? How long do effects last?

it takes time to synthesize factors so it won’t work right away because the liver needs to make it

the effects are long lasting

What is kCentra, how quickly does it work, and how long does it last?

a vit K dependent factor

it works QUICKLY but does not last as factors are degraded

Which 2 interactions lead to increased Vitamin K and how does this impact bleeding/thrombosis/INR?

1. CYP 2C9 INDUCERS

2. INCREASED dietary Vit K

causes a DECREASED warfarin effect → increased clotting risk, decreased bleeding, decreased INR

Which 2 interactions lead to decreased Vitamin K and how does this impact bleeding/thrombosis/INR?

1. CYP 2C9 INHIBITORS (prevents warfarin metabolism)

2. DECREASED dietary Vit K

causes an INCREASED warfarin effect → decreased clotting risk, increased bleeding, increased INR

What is the name of the ORAL DTI?

Dabigatran

What is the route of administration for Dabigatran?

oral administration

What is the MOA of Dabigatran?

DIRECTLY inhibits II_a (thrombin)

Which titration lab is required for Dabigatran?

no labs required!

How is PT, PTT, and anti-X_a impacted?

PT: increased

PTT: increased

anti-X_a: none

What is the AE of Dabigatran?

bleeding

What is the reversal agent?

Idarucizumab

How does Idarucizumab work?

it is an antibody that works directly against dabigatran

What does the suffix -xaban mean?

direct X_a inhibitor

what is the name of the direct X_a inhibitor?

Rivaroxaban (x is banned)

What is the route of administration of Rivaroxaban?

oral

What is the MOA of Rivaroxaban?

DIRECTLY inhibits X_a

Which titration labs are required?

none!

How is PT/PTT/anti-X_a impacted?

PT = increased

PTT = increased

Anti-X_a = detected