Antiplatelets, Anticoagulants, And Fibrinolytics

Ticagrelor is unique among the antiplatelets in that it is reversible. It is also a non-thienopyridine, and must be used with low-dose aspirin.

Acidic and neutral drugs bind to albumin, which is basic. Basic drugs bind to alpha-1 acid glycoprotein. Oxygen binds to hemoglobin. Warfarin binds to albumin at greater than 95%. These are facts. Thus, if a patient has another drug on board that displaces warfarin from albumin, there will be more free warfarin and more anticoagulation. Something to consider.

This is true; fondaparinux requires antithrombin in order to inhibit Factor Xa; this inhibition results in less conversion of prothrombin to thrombin and less conversion of fibrinogen to fibrin.

Heparin can only prevent further clotting; it cannot dissolve a clot. You will need a clot-buster, aka a fibrinolytic such as tPA (alteplase/Activase) to break up an active clot. This is due to heparin's mechanism of action, which has an indirect effect on thrombin via antithrombin; thrombin eventually converts fibrinogen to fibrin, which solidifies a clot. By stopping thrombin, you can stop more fibrin from solidifying the clot, but heparin cannot get into and bust up a clot.

Please note that aspirin can be used for primary prophylaxis in appropriate individuals.

The answer is 5-10 days for the lifespan of platelets. This has implications for the use of irreversible anti platelet medications, which will have effects even when discontinued due to the time necessary for platelet regeneration. A normal platelet count is 150,000 to 400,000 per microLiter, which can be abbreviated as "150" to "400." Platelets are normally smooth, but have glycoproteins that can assist in the aggregation and formation of a clot.

The inhibition of CYP 2C19 by drugs such as omeprazole, a PPI (proton pump inhibitor), will lead to less conversion of clopidogrel (a prodrug) to its active metabolite, and less antiplatelet activity. If a PPI is required, pantoprazole is the drug of choice due to less inhibition of CYP 2C19.

The gold standard of glycoprotein IIb/IIIa inhibitors, abciximab (Reopro) is reversible by overwhelming the agent with platelets. The other agents (eptifibatide and tirofiban) are not reversible, have renal dosing, and are shorter-acting.

Ticagrelor has interactions with both CYP 3A4 inhibitors and inducers; thus, it may have several clinically significant drug-drug interactions. As a result, the maximum doses of simvastatin and lovastatin are 40 mg to prevent the incidence of rhabdomyolysis.

This is a niche role for aspirin/dipyridamole (Aggrenox) and its only FDA-labeled indication.

The heparin/LMWH bridge is necessary due to the depletion of proteins C and S, which are anticoagulant proteins, before the other Vitamin K dependent clotting factors (2, 7, 9, 10). Thus, warfarin without the bridge could lead to a clot with initial therapy.

A white clot is platelet rich and is subocclusive; only when fibrin comes to further solidify the clot is it fully occlusive. The difference between subocclusive and occlusive will play out in NSTEMI vs STEMI. As you could logically assume, the NSTEMI is subocclusive and the STEMI is occlusive.

While there are many nomograms and tools for dosing warfarin, this is a rule of thumb for adjusting warfarin doses.

By inhibiting the final common pathway for platelet aggregation at greater than 80% of receptor occupancy, these extremely potent agents are used during a PCI to prevent clotting. Basically, the platelets cannot hold hands and form the clot, so the patient is spared further clotting.

Cilostazol (Pletal) has a unique niche in being useful for the treatment of intermittent claudication symptoms due to peripheral arterial disease (PAD). This is its only FDA-labeled indication. Of note, avoid cilostazol in heart failure patients.

Streptokinase is less specific than tPA for clot-bound fibrin, and thus binds equally to circulating and the clot-bound plasminogen, resulting in more systemic bleeding. Therefore, tPA is preferred over streptokinase for dissolving coronary and cerebral vascular thrombi. Fun fact: streptokinase is derived from streptococci (the bacteria), so patients with a recent strep infection will need a higher dose!

If a patient has a reversible risk factor, such as a 16 hour flight that resulted in a DVT or a long bone fracture, then treatment for only 3 months is preferred. If the risk factor is not reversible, such as prolonged immobility due to a car accident, then treatment for 6-12 months is necessary. For patients with a recurrent (second) event, or who have a hypercoagulable disorder (ex: proteins C and S deficiency), then lifelong prophylaxis is indicated.

With vitamin K intake, always educate your patients to maintain a CONSISTENT intake of vitamin K. More vitamin K will lead to more clotting, but the patient can still eat their leafy green vegetables, since their increased intake was factored into their maintenance dosing.

Fibrinolytics are also know as tissue plasminogen activators, and as such they activate plasminogen to plasmin, which then breaks up fibrin, but also breaks down fibrinogen, thus preventing more fibrin from forming. However, tPA is more specific for clot-bound fibrin than for fibrinogen. Breaking down too much circulating fibrinogen could lead to systemic fibrinolysis, which would not be good.

While the usual dose of apixaban for non-valvular atrial fibrillation is 5 mg PO BID, if the patient has 2 of the following (age > 80, body weight 1.5mg/dL), then the dose should be 2.5 mg PO BID. If a patient is on a CYP 3A4 or P-gp inhibitor, then the dose should be 2.5 mg PO BID. If the patient is on the CYP 3A4/P-gp inhibitor and is eligible for the 2.5mg PO BID dosing due to their age, weight, or serum creatinine, then the patient cannot take apixaban.

The dosing of heparin depends of the indication. Note the SC route for prophylaxis. The dose of heparin for ACS treatment has a max of 4,000 units for the bolus and 1,000 units/hr for the continuous infusion.

Rivaroxaban is contraindicated for VTE prophylaxis if the patient's CrCl is less than 30 and for non-valvular A. fib if the CrCl is less than 15 ml/min. There is no routine monitoring and it is metabolized by CYP 3A4 with some renal elimination.

A key point here is that direct thrombin inhibitors can get into clots and exert an effect on thrombin. In general, the direct thrombin inhibitors bivalirudin and argatroban are a good alternative to heparin or a glycoprotein IIb/IIIa inhibitor for PCI management.

Warfarin inhibits the enzyme "Vitamin K Oxide Reductase", which normally takes oxidized Vitamin K and reduces it in order for the reduced form to assist in the conversion of a prothrombin precursor to prothrombin. Less prothrombin means less thrombin, and less thrombin means less conversion of fibrinogen to fibrin. Warfarin inhibits the synthesis of the vitamin K dependent clotting factors (2, 7, 9, 10) and the ANTICOAGULANT proteins C and S. Since the anticoagulant proteins are inhibited first (shortest half lives), starting warfarin without a heparin or LMWH bridge can INCREASE the risk of clotting.

Weight is used to determine the dose for treatment of VTE; for prophylaxis dosing, a weight less than 50kg results in the contraindication of fondaparinux. Indication (prophylaxis vs treatment) determines the dosing choices, which are then based on weight for treatment. Renal function is not used to determine dosing, but plays a role in that a CrCl of less than 30ml/min results in the contraindication of fondaparinux. As far as I know, prior use of fondaparinux does not affect its use.

Mechanical valves have greater risks of developing clots, and mitral valves have greater risks of clots due to the lower pressure compared to in the aorta. Therefore, the mechanical mitral valve requires a goal of 2.5-3.5. If a patient has both mechanical mitral and aortic valves, use the goal of 2.5-3.5.

VTE prophylaxis dosing differs from the VTE treatment dosing. As always, there is renal dosing for prophylaxis with enoxaparin; for CrCl less than 30ml/min, instead of 40mg SC Q24 hr, use 30mg SC Q24 hr. For VTE treatment, instead of 1.5mg/kg/day SC or 1mg/kg SC Q12 hr, use 1mg/kg/day. For ACS, instead of 1mg/kg SC Q24 hr, use 1mg/kg/day SC. Avoid if patients are on dialysis.

INR is the international normalized ratio, which is a normalization of the different PT tests. It tests the extrinsic pathway, which is activated due to external trauma that causes blood to leave the vasculature. The aPTT is the activated partial thromboplastin time, and measure the intrinsic pathway, which is activated due to injury within the vasculature. Both pathways meet in the common pathway and result in the conversion of fibrinogen to fibrin, which is an insoluble clot. Heparin can also use the ACT, or activated clotting time, for monitoring in the OR or cath lab, due to the short half life. LMWH such as enoxaparin does not require monitoring, but if so desired, anti-factor Xa concentrations can be measured and quantified.
Due to the predictable effects of anticoagulation, fondaparinux, rivaroxaban, and apixaban do not require routine monitoring.