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.
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 drugs reduce hypercoaguability by decreasing surface expression of GPIIb/IIIa and additionally vasodilates?
PDE inhibitors: Dipyridamole and cilostazol. Dipyridamole inhibits phosphodiesterase, increasing amount of cAMP and thus decreasing surface expression of GPIIb/IIIa. Additionally, it increases cGMP levels and causes vasodilation.
When is dipyridamole usually indicated for use?
Adjunct therapy with aspirin or warfarin.
A patient has come to the clinic for angioplasty and has not taken his aspirin or warfarin for a week. What drugs could you administer IV that will affect the platelets ability to bind fibrinogen? Which is a monoclonal antibody and which is contraindicated for people with renal insufficiency?
Direct GPIIb/IIIa blockers: Abciximab (monoclonal antibody), Eptifibatide (renally cleared), and Tirofiban.
What classes of drugs do we use to target secondary hemostasis?
Warfarin, Heparins, factor Xa inhibitors, thrombin inhibitors.
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.
When might you use heparin and why wouldn't you administer it IM or orally?
It is used for recurrence of stroke/MI and embolisms. You only administer it IV or subcutaneously because it will cause hematomas anywhere outside of the blood stream.
How do low molecular weight heparins (LMWH) differ from unfractioned heparin? What are the LMWH drugs?
LMWH have clipped off the thrombin binding site and only target factor Xa. Drugs are fondaparinux, enoxaparin, dalteparin and tinzaparin.
A patient comes to the ED suffering from a pulmonary embolism. You administer heparin and the patient dies from massive platelet destruction and clotting. What happened and what drug could have been used without this side effect?
This is a case of HIT (heparin-induced thrombocytopenia). He had an autoimmune reaction that destroyed platelets and activated other platelets causing clotting. Use of fondaparinux does not have this risk because the thrombin-binding domain is not present.
Is pregnancy a contraindication for heparin therapy?
No, it does not cross the placenta.
What is the downside to using LMWH?
There is no antedote in the case of LMWH overdose. With unfractionated heparin you can reverse its effects with protamine sulfate.
A patient comes to the ED suffering from pulmonary embolism. You administer heparin he begins to show fatal signs of HIT (heparin-induced thrombocytopenia). What drugs are indicated for use in this condition?
IV direct thrombin inhibitors: lepirudin, bivalirudin, argatroban. These all inhibit thrombin directly and do not require activation of anti-thrombin.
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.
When would you use warfarin?
Prophylaxis for DVT, PE, a-fib and heart valve, recurrence of MI replacements.
Why is warfarin difficult to dose?
It has a narrow therapeutic window and many people have varying levels of serum albumin, which 99% of warfarin binds to. Additionally, polymorphisms exist in metabolism of warfarin itself and in VKER.
A patient lives way out in the boonies and needs warfarin therapy. What new drugs could you consider that would not require him to have his INR checked regularly?
Dabigatran (direct oral thrombin targeter), Rivaroxaban (direct on factor Xa) and Apixaban (direct on factor Xa).
What is the target INR range for warfarin?
What thrombolytic drug works directly on a clot that has formed?
tPA (tissue plasminogen activator). This drug only works when plasminogen is bound to the clot, it is then converted to plasmin and begins breaking fibrin bonds.
What thrombolytic drug would you use if there were clots everywhere and you didn't care about specificity for fibrin? What if you only wanted thrombolytic therapy at the site of the clot?
Urokinase is a thrombolytic drug that activates all plasmin. t-PA is only activated by fibrin and will thus be specific for a clot. Streptokinase is between the two because it needs plasminogen pro activator to activate plasmin.
When would you use a thrombolytic drug?
Acute MI, stroke, PE or DVT.
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.