10b Coagulation Disorders

HTHSCI 2H03

What happens when there is damage to a vessel?

- injury
- spasm
- platelets cover hole
- fibrin provides scaffolding for clot

How does the body get rid of a clot?

- 24-48 hr after clot
- release Tissue Plasminogen Activator (t-PA)
- converts plasminogen --> plasmin
- plasmin digest fibrin, destroys clot

Blood clots are formed through the action of which 2 processes?

1. coagulation cascade
2. activation of platelets

What are thrombolytic disorders?

- formation of non-therapeutic clots
- ex AF

How can you prevent clot formation? mechanism and drug class?

1. Inhibition of clotting factors

a) anticoagulant

2. Inhibition of platelet actions

a) anticoagulant/antiplatelet

How can you remove a existing clot? mechanism and drug class?

- dissolve clot
- thrombolytic

What are the 5 types of anti-coagulant drugs?

1. Heparin
2. Warfarin
3. Low Molecular Weight Heparins (LMWH)
4. Direct Thrombin Inhibitors
4. Direct Xa Inhibitors

What is the MOA of heparin?

- enhances ability of antithrombin III to inactivate
- Thrombin --> no conversion of fibrinogen to fibrin
- Xa --> inhibits intrinsic and extrinsic clotting pathways

Why is heparin only used in hospital?

- blocks thrombin and Xa

- higher risk

- more monitoring

What is the MOA of LMWHs?

- same as heparin
- mostly Xa
- therefore can be used in the community

What is the MOA of warfarin?

- inhibits epoxide reductase
- decrease body's ability to recycle VitK
- needed for synthesis of active clotting factors

How does it take for warfarin to start working? Why is this significant?

- 3 days
- overlap with heparin therapy for 3 days before discharge
- very high risk for bleeding

What are 2 signs of internal bleeding?

- low RBC
- low BP

What is MOA direct thrombin inhibitors?

directly and reversibly binds to and inhibits thrombin

What is antidote for direct thrombin inhibitors?

- Praxbind
- direct thrombin inhibitors would rather bind to praxbind distracting it from thrombin

What is the MOA of direct Xa inhibitors?

- Bind factor Xa--> prevent conversion of prothrombin to thrombin
- no effect on platelets

What is the antidote for direct Xa inhibitors?

- Andexxa
- direct Xa inhibitors would rather bind to andexxa distracting it from factor Xa

Which drug class has begun to replace warfarin and some LMWHs? Why?

- Direct Xa Inhibitors

- orally administered

- predictable

- less monitoring

- fewer drug interactions

How is bleeding monitored?

1. International Normalized Ration (INR): prothrombin levels

2. Prothrombin Time: time required for clotting to occur

What are the three types of antiplatelets drugs? Which is rarely used?

1. Irreversible cyclooxygenase inhibitors (ASA)

2. ADP Rc Antagonists

3. Glycoprotein IIb/IIIa Rc Antagonists *IV only, rarely used

What is the MOA of ASA?

- irreversibly blocks COX1/2 enzymes
- inhibits synthesis pf prostaglandins (thromboxane A2)

Who is ASA beneficial for? Who is to not?

Beneficial: established CVD
No Benefit: no evidence of CVD --> increased risk of bleeding

What is the MOA of ADP Rc antagonists?

- irreversibly changes molecular conformation of ADP Rc on platelets
- platelets no longer receive chemical signal to aggregate
- inhibits thrombus formation

What is the MOA of glycoprotein IIb/IIIa Inhibitors?

- normally glycoprotein IIb/IIIa is a Rc found on platelets
- activation causes binding to fibrinogen and aggregation
- antagonist prevents this

What is the route of admin for these?

- IV only
- in cath lab

What drug classes dissolves thrombus'?

Thrombolytic drugs

What is the MOA of thrombolytic drugs>

- converts plasminogen to plasmin
- promotes fibrinolysis
- dissolve fibrin

What is a risk of thrombolytic drugs?

- dissolves all clots
- therapeutic or not
- high risk with traumas

Which thrombolytic drug is no longer used, why?

Streptase

- caused allergic reaction

- one time use

What was developed instead?

Tissues Plasminogen Activator

- identical endo tPA that dissolves clots

- specific to fibrin bound plasminogen (no systemic effects)

What are antifibrinolytic drugs used ofr?

- facilitae blood clotting
- shorten bleeding time
- p/o bleeding

What is the MOA of antifibrinolytics?

- enzyme inhibitor
- inactivates plasmin
- prevents dissolution of fibrin