Pharmacology-Hemostasis, Anti-Coagulants, Thrombolytics Flashcards
What molecules contribute to the normal anti-thrombotic state of the vasculature?
Antithrombin, protein C, protein S and PGI2.
What happens after endothelial injury that leads to development of a clot?
Endothelin release by endothelia -> vasoconstriction -> platelets adhere to vWF and collagen -> platelet gets sticky and degranulate -> ADP and TXA2 release -> platelet recruitment and white plug formation -> Tissue factor release -> thrombin activated -> fibrinogen clipped -> red clot formation.
Coagulation cascade
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How does our body prevent formation of really large clots and break down large clots?
t-PA (fibrinolysis) or thrombomodulin (blocks coagulation cascade)
Where do platelets come from and where are they stored?
They break off of megakaryocytes and are stored in the spleen. They have a life span of about 10 days.
Why is the stain shown in this image significant in combating coagulation disorders?
It is the GPIIb/IIIa fibrinogen receptor on platelets. This receptor is what allows platelets to bind fibrinogen and form the meshwork of the clot.
What molecules released from the platelets result in the “feed forward loop” causing mass platelet aggregation and thrombus formation?
ADP, 5-HT and TXA2
What are the four classes of drugs we use for anti-platelet drug therapies (targeting primary hemostasis)?
COX inhibitors, ADP antagonists, PDE inhibitors and GP IIb/IIIa inhibitors
In what part of this platelet’s metabolism does aspirin work?
In a normal cell, binding of vWF causes activation of PLC/PL-A2 which cleaves arachidonic acid. COX-1 then converts it to TxA2 which propels the feed forward loop of platelet aggregation. Aspirin prevent COX-1 and decreases platelet aggregation and degranulation.
Why must patients be off of aspirin for 7-10 days prior to an operation?
It is an irreversible inhibitor of COX1 and COX2. Since platelets do not have nuclei, it inhibits COX for the life of the platelet, which is 7-10 days.
Why do you only need low dose aspirin to inhibit thrombosis? What happens at high doses of aspirin?
Aspirin is rapidly absorbed into the blood and platelets reside in the blood. At high doses, you also inhibit endothelial COX-1 receptors that make PG12 and normally inhibit platelet aggregation via vasodilation. You want to keep it at low doses so you have both anti-platelet effects.
Why aren’t NSAIDs as effective for platelet aggregation as aspirin is?
They competitively inhibit COX.
What side effects must you be aware of with aspirin?
GI bleeding, allergies, and Reye’s syndrome in children.
Why is eating fish preferential to eating corn if you are hypercoaguable? Is it worth eating fish if you are on prophylactic aspirin therapy?
Fish has omega-3 fatty acids which lead to production of TXA3 which is an anti-inflammatory and vasodilator. Corn has omega-6 fatty acids that product TXA2 and PGE2 which induce platelet aggregation and vasoconstriction. Aspirin blocks COX-1 so it will block all effects by these omega fatty acids.
A patient just had an acute MI and a stent put in after angioplasty. What anti-platelet drugs could you prescribe to minimize clot formation while he recovers?
Thienopyridines (clopidogrel or prasugrel), you permanently block the P2Y12 (ADP receptor). This leads to long-lasting increases in cAMP and a decrease in surface expression of GPIIb/IIIa.
Why might a patient taking clopidogrel or ticlopidine have little to no anti-coagulant effects and increased side effects? What drug might you want to try with these patients?
These drugs are prodrugs and must be metabolized by CYP450. Administration of omeprazole will impair CYP450 and block prodrug conversion, increasing side-effects. Patients may also have polymorphisms in CYP450 that inhibit prodrug conversion. You could try ticagrelor, which is not a prodrug.
What is an ideal aPTT (activated partial thromboplastin time) and what does it measure? PT (prothrombin time) and what does it measure?
aPTT = 22-40 seconds, it measures the intrinsic pathway that is most often affected by heparin. PTT = 10-14 seconds, it is a measure of the extrinsic pathway and is most often affected by warfarin.
Why wouldn’t you measure heparin activity with an INR or PT? What is your target level for someone on heparin therapy?
Heparin binds and enhances antithrombin protein which inhibits thrombin and factor Xa. This pathway is not in the extrinsic pathway measured by PT/INR.
How does heparin potentiate the activity of antithrombin?
It binds it, increases its activity and allows for formation of the anti-thrombin/thrombin complex. Heparin then detaches and goes elsewhere.
Why does warfarin take so long to start working? How do you monitor your maintenance dose as someone beings therapy?
It drives the formation of inactivated clotting factors II, VII, IX and X as they are synthesized. It takes a long time for the pre-existing factors to degrade and thus a long time for the factors affected by warfarin during synthesis to incorporate into the clotting cascade. You monitor the effects of warfarin via INR during the initial phase.
Why does eating seaweed (high in vitamin K) antagonize the effects of warfarin?
Warfarin works via vitamin K depletion by inactivating vitamin K-epoxide reductase. Loss of vitamin K leads to an inability to synthesize activateable coagulation factors. Adding vitamin K through the diet contradicts the effects of warfarin.
A patient comes to see you with a history of bleeding easily. His family also has similar issues. How could you treat this patient?
Find out what clotting factor is deficient and provide replacement therapy. (Usually factors XIa, IXa or VIIIa)
A 32 year old female comes to the ED after a severe car accident and is hemorrhaging from multiple places. You are having difficulty controlling the bleeding.
Fibrinolytic inhibitors (tranexamic acid and aminocaproic acid (EACA)). You also may give factor VIIa in the future.
