Module 25

Question 1

What is the chemical mechanism by which warfarin inhibits coagulation? What is the time course of the anticoagulation?

Answer 1

• The structure of warfarin is related to the structure of vitamin K. Vitamin K is required for the synthesis of clotting factors in the liver by adding a carboxy group to precursors to produce active clotting factors as shown below (it involves an interesting epoxide form of vitamin K). Warfarin inhibits this conversion.
  
  • Given that it inhibits the synthesis of clotting factors, it does not have an immediate effect on clotting, and the time to onset is a function of the half-lives of the clotting factors. The approximate half-lives of the clotting factors are: factor VII, 6 hours; factor IX, 24 hours, factor X, 36 hours; and factor II, 50 hours.
  • Vitamin K is also associated with the synthesis of anticoagulant factors: protein C with a half-life of 8 hours and protein S with a half-life of 30 hours.

Question 2

What are the mechanisms by which other drugs interact with warfarin? What is the overall effect of drugs that displace warfarin from binding to serum albumin? What is the mechanism by which antibiotics can increase the anticoagulant effect of warfarin?

Answer 2

• Warfarin has a very narrow therapeutic range; therefore, small effects can result in either bleeding or lack of therapeutic effect. The effects can be pharmacokinetic or pharmacodynamic.
  
  • The major P450 involved in the clearance of warfarin is CYP 2C9. Therefore, any other drug that inhibits or induces CYP 2C9 will affect the optimal dose of warfarin.
  • The effect of displacing drugs from protein binding is complex because it not only increases the free fraction to exert a pharmacological effect, it also increases the free concentration for clearance.
    ○ Therefore, a decrease in protein binding shortens the half-life of the drug unless it is a very high clearance drug (The rate of clearance of high clearance drugs depends on blood flow rather than free concentration because the drug that is protein bound can be stripped off of the protein as it travels through the liver or kidney).
    ○ Warfarin protein binding is high (99%), and it is not a high clearance drug, so displacement from protein binding will significantly increase the free fraction, and although the clearance will also increase, the net effect is to increase the anticoagulant effect of warfarin.
  • Warfarin competes with vitamin K; therefore, anything that affects vitamin K levels will also affect the anticoagulant affect of warfarin.
    ○ Therefore, dietary vitamin K found in leafy green vegetables can have an effect on warfarin anticoagulation. This led some clinicians to tell patients to avoid leafy green vegetables; however, a recent study suggests that regularly eating green vegetables leads to a more stable INR (international normalized ratio, the usual measure of anticoagulation).
    ○ In addition, some bacteria can also synthesize vitamin K; therefore, antibiotics can affect warfarin anticoagulation by decreasing vitamin K synthesis.

Question 3

How would you treat a patient on warfarin who developed a serious intracranial bleed?

Answer 3

• Fresh frozen plasma or human prothrombin complex (Octaplex) would be most appropriate because it contains the clotting factors. Vitamin K would reverse the effects of warfarin, but it would take days to synthesize sufficient quantities of the clotting factors

Question 4

What is believed to be the mechanism by which warfarin can cause skin necrosis, and when is it likely to occur?

Answer 4

• Because warfarin also inhibits the anticoagulant factors, protein C and protein S, and protein C has a short half-life, early in the treatment with warfarin there can be a procoagulant effect, and clotting in the skin is responsible for skin necrosis.
  
  • Consistent with this hypothesis, it usually occurs early in the course of warfarin anticoagulation.

Question 5

Contrast the effects of heparin and warfarin on coagulation. How does this affect the methods by which the anticoagulation is monitored for these two drugs?

Answer 5

• The clotting system is quite complex, and I would not ask much detail on an exam.
  
  • Heparin has no intrinsic anticoagulant activity; what it does is bind to antithrombin and markedly accelerate the rate that antithrombin inhibits various coagulation proteases, especially thrombin, IXa, and Xa of the intrinsic pathway.
    ○ The major effect is to increase the activated partial thromboplastin time (aPTT); it has less effect on the prothrombin time.
    ○ High doses of heparin also affect platelet aggregation and prolong the bleeding time.
  • In contrast, warfarin inhibits the synthesis of multiple vitamin K-dependent clotting factors: II, VII, IX, and X, and a major effect is on factor VII of the extrinsic pathway.
    ○ Therefore warfarin anticoagulation is monitored by its effect on the prothrombin time, which is now expressed as an international normalized ratio (INR) of prothrombin time of the patient relative to a standard. Levels of IX or proteins S and C have no effect on the INR.

Question 6

The treatment of deep vein thrombosis (DVT) usually involves heparin for the first 3 days until warfarin takes effect. Heparin must be given iv and requires close monitoring. It, therefore, generally requires hospitalization. What is the difference in the mechanism and the major mode of clearance of regular and low molecular weight, and how does this difference make possible to treat with low molecular weight heparin outside of the hospital?

Answer 6

• Heparin is large and is cleared mostly by the reticuloendothelial system, e.g. taken up by macrophages, and this clearance is saturable. Because the clearance is saturable, a small increase in dose can lead to a large change in the degree of anticoagulation.
  
  • In contrast, low molecular heparin is smaller, and the major clearance is renal and is not saturable. Therefore its effects are more predictable.
    ○ In addition, its effects are more on factor Xa with less effect on thrombin, which means that low molecular weight heparin has less of an effect on the aPTT; therefore, monitoring by aPTT is less useful.
    ○ Given the more predictable effect and the decreased need for monitoring, low molecular weight heparin is easier to use and can be used outside of the hospital.

Question 7

How can heparin lead to hypercoagulability and thrombocytopenia?

Answer 7

• Heparin binds to platelet factor 4. Some patients develop antibodies that bind to this complex, and these antibodies cause platelet aggregation. This causes both thrombosis and thrombocytopenia, which can cause bleeding. With increased clotting, but also an increased risk of serious bleeding, it is a challenge to deal with. Even though this is an immune-mediated adverse reaction, there is no immune memory. Once the antibodies are cleared, which takes about 100 days, if the patient is rechallenged, usually there is no recurrence of thrombocytopenia, and if it does recur, it takes as long as on initial exposure. Although low molecular weight heparin can also cause thrombocytopenia, the incidence is less: <1% incidence for low molecular weight heparin compared to up to 5% with heparin.

Question 8

What are rivaroxaban, apixaban, and edoxaban, and how do they work? What are advantages and disadvantages relative to warfarin?

Answer 8

• These agents are direct Xa inhibitors. The advantage is that they are much easier to use because the dose/response effect is much shallower, and therefore the risk of under or over anticoagulation is much less
  
  • They appear to be associated with a lower risk of serious bleeds than warfarin, but there is no antidote to reverse the effects in the case of a serious bleed or emergency surgery.
    In contrast, an antibody to dabigatran called idarucizumab has been developed that binds to and inactivates dabigatran and reverses its anticoagulant effect. Although they do not require monitoring, the disadvantage is that there is no simple way to determine the degree of anticoagulation of patients on these drug

Question 9

What agents are commonly used to reduce mortality associated with a heart attack, especially after placing a coronary artery stent during an acute MI, and how do they work? Compare the half-life of the drugs and their duration of action.

Answer 9

• There are two types of drugs used for this indication, often in combination. They are aspirin and thienopyridine-class antiplatelet agents. The target for both types of drugs is platelet aggregation.
  
  • Aspirin inhibits thromboxane synthesis as discussed elsewhere. The thienopyridines inhibit the receptor P2Y12. The thienopyridines include ticlopidine, clopidogrel, and prasugrel.
    These drugs are prodrugs and require oxidation of the thiophene ring to form a reactive intermediate that irreversibly binds to P2Y12 and inhibits platelet aggregation. Because the binding is irreversible, the duration of effect is much longer than the half life of the drugs.