3 Mousa Suboh Osama Alzoubi (OZ) Malik Zuhlof 1 P a g e
In the last lecture we talked about the anticoagulants, we talked about heparin and we said that it has 2 types: one that has long stretch of polysaccharides and it is heterogeneous so to fix this problem of heterogeneity we produced the second type which is the low molecular weight heparin (LMWH) or fractionated heparin, by using this type we reduced a lot of problems including: 1- aptt (the monitoring process of heparin). 2- Hospitalization 3- HIT (heparin induced thrombocytopenia). 4- Osteoporosis 5- Incidence of bleeding, because the fractionated heparin inactivates factor Xa and doesn t affect thrombin. Despite the reduction in the afore mentioned side effects, it is not the best solution for the patient to take the drug by injection especially when they should take it for a long time (6 months for example) like the patients with DVT, pulmonary embolism or the patients with prosthetic heart valves, in which they have to take it orally, for this reason the very old drug Warfarin was produced, (Which was the only oral anticoagulant until the year of 2000, after that other oral anticoagulants were manufactured). Also, we talked about the synthesis of the clotting factors in the figure below and how they are inhibited by the oral anticoagulants and we talked about the pathway of vitamin k that activates vitamin K dependent factors (II, VII, IX, X, protein C, S) which are inhibited by warfarin. 2 P a g e
Warfarin Warfarin is an old drug. It is active in the veins more than the arteries which is a great advantage as the thrombi usually form in sluggish blood الراكد) (الدم which is in the veins. Blocks carboxylation and subsequent activation of factors VII, IX, & X, & II as well as the proteins C and S (proteins C and S are anticoagulants and protein S is a cofactor to protein C). This blockade results in incomplete molecules that are biologically inactive in coagulation. So, warfarin has coagulation and anticoagulation effects but the anticoagulation effect is much higher. For example, when we give a patient warfarin and the activity of it reaches the maximum (steady state of activity) it blocks the carboxylation of factors VII, IX, & X, & II much more than proteins C and S so the net effect will be anticoagulation because we are losing the activity of the coagulation factors much more than that of the anticoagulation factors. Mechanism: Vitamin K is needed as a cofactor for the Carboxylation of Factors VII, IX, & X, & II, proteins C and S, but once they are carboxylated, Vitamin K is Oxidized and Deactivated to Vitamin K epoxide, and for more carboxylation, Vitamin K epoxide should be reduced back by Vitamin K Epoxide Reductase to Ordinary Vitamin K, here comes Warfarin which prevents reductive metabolism of inactive vitamin K epoxide back to vitamin K. For example, In order to convert decarboxylated prothrombin to prothrombin (factor II), we need vitamin K as a cofactor, so we have a coupled reaction in which Vitamin K is Oxidized and Deactivated to Vitamin K epoxide in order to co-activate the carboxylase enzyme to convert descarboxy-prothrombin into prothrombin, and in order for the process to continue it should return back to vitamin K which is done by the action of 3 P a g e
vitamin K epoxide reductase, so if we give the patient vitamin K, the production of prothrombin will increase which increases the coagulation (vitamin K is a coagulant), on the other hand an anti-vitamin K like warfarin is an anticoagulant because it inhibits vitamin K epoxide reductase and this prevents vitamin K epoxide to return back to vitamin K. Conclusions: 1. if vitamin K increased in our body there will be coagulation and if it reduced there will be anticoagulation. 2. Warfarin is a vitamin K epoxide reductase inhibitor, so the vitamin K dependent coagulation factors (VII, IX, & X, & II) will not be activated so the coagulation cascade will be inhibited. 3. Also, we inhibited the activation of proteins C and S but as we said before warfarin acts mainly on factors VII, IX, & X, & II so the net result will be anticoagulation effect. But we have a problem, in the blood there are a lot of clotting factors that are already activated, so the warfarin has to wait until the half-lives of these activated factors to be reached so that they will be degraded and 4 P a g e
5 P a g e decayed, in order to work on the inactivated factors and inhibit the process of carboxylation preventing the production of activated ones. (Note: The most important one to wait for to be degraded is factor II, because it s at the end of the coagulation cascade, and even if other previous factors were degraded, as soon as factor II is active, thrombosis is active too) Full therapeutic effect of warfarin is not achieved until existing activated factor II is cleared (t1/2 of factor II is 60 hours). So all of the afore mentioned factors have different half-lives, factor II has the longest halflife, so in order to reach the maximum effect of warfarin (anticoagulation effect), Activated factor II has to be cleared from the blood, and by that, the inhibition of producing the mentioned factors will be at the maximum because all of the activated ones in the blood have been degraded so the anticoagulation effect of the warfarin will be at the maximum. In order for the activated prothrombin in the blood to be degraded fully, it has to reach its half-life three times so in other words the patient has to stay in the hospital for five days after taking warfarin because activated factor II has to be nearly fully degraded before warfarin reaches its maximum effectiveness and real anticoagulant activity. Another problem is when we give the patient warfarin, the half-lives of protein S and C are short, which means that they will be cleared quickly from the blood, add to that Warfarin is inhibiting the carboxylation and activation of new Protein S and C, so there will be a period of time in which our body is having very low levels of active protein S and C, and simultaneously, we will have higher levels of activated clotting factors that still aren't degraded due to their higher half-life, which means we shifted the balance to coagulation for a period of time (which is between the maximum effect of warfarin and until activated protein C and S are degraded fully) which is after 2-3 days from giving warfarin. The solution for the coagulation effect problem is that heparin or enoxaparin must be overlapped with warfarin & continued for 4 5 days until an INR between 2.0 and 3.0 is reached (INR will be explained later but
6 P a g e it is basically until the warfarin activity is steady) and by that we avoid thrombosis, this is called bridging therapy. An example on bridging therapy for better understanding, when we give a patient DMART (disease modified anti rheumatoid arthritis) drugs, they need 6 weeks to start working, during these six weeks we give the patient cortisone until DMART start working. We have 2 polymorphisms that affect Warfarin s activity: 1. Vitamin K epoxide reductase is highly polymorphic, this means that it has a lot of pharmacogenetics, which means there is a lot of diversity between the patients in this enzyme, for example in the Jordanian society, 25% of the population have polymorphism that reduce the activity of vitamin K epoxide reductase, that s why warfarin works on some patients better than others because for example in the mentioned polymorphism the activity of the enzyme is already low so warfarin s effect will be much stronger. 2. Warfarin get metabolized by CYP2C9 which is one of the cytochrome P450 family. CYP2C9 is polymorphic, this polymorphism leads to reduction of CYP2C9 activity, 10-12 % of the Jordanian population have this polymorphism so there will be intermediate or full metabolizers of warfarin in the population. The 2 polymorphisms mentioned above control the effect of warfarin whether it is strong or weak. In order to solve this variation problem, we have to find a way like aptt to monitor prothrombin time (PT) in the patients which is a very important indication to warfarin activity. If warfarin s activity is high the PT will be longer so the anticoagulation effect will be stronger. In order to use prothrombin time (PT) to monitor warfarin s activity we normalize it (Titrate it, the same idea in aptt used to monitor heparin), so
it becomes international normalized ratio (INR) which is PT of a patient divided by PT of other 1000 patients in the same population *100% ( I think the Dr said *100 By mistake, as we will see the calculated explained the warfarin example without multiplying by 100 ) INR= PT of patient Average PT of 1000 patients in population 100% (Which you can say is the Normal PT in a popluation) We use INR to monitor warfarin s activity because there is high variation between populations in response to warfarin, for example, some patients might bleed after taking warfarin so the INR will be high, other might not respond to warfarin so the INR will be low. Now after we explained INR we should be able to understand the vague sentence from before, heparin or enoxaparin must be overlapped with warfarin & continued for 4 5 days until an INR between 2.0 and 3.0 is reached, INR between 2 and 3 which means PT is multiplied by 2 or 3 compared to the normal Average PT in the population, which means there is a strong Anticoagulant effect, which means that warfarin has reached its maximum Anticoagulant effectiveness and its safe now to stop heparin or enoxaparin. So, the normal range of INR should be between 2 3 in the patients for example with pulmonary embolism or DVT and it may reach 3.5 4.0 in patients with prosthetic heart valves. Vitamin K rich Diet problem In Jordan: Sometimes, coagulation happens with patients that are taking warfarin! This may happen as a result of eating food that is rich in vitamin K like parsley, broccoli and Rocca (.(جرجي And as we know, the whole mechanism of Warfarin depends on preventing the reduction of Vitamin K epoxide back to Vitamin K, So if you take lots of Vitamin K in your diet, it s as if Warfarin is not functioning. Another problem is that most of the patients that enter the emergency room for bleeding side effect is from Warfarin; because as we mentioned in the past point, Vitamin K rich diet opposes Warfarin's action, so these patients after suffering from coagulation due to their diet, they will be 7 P a g e
given a higher dose of Warfarin, and if the patient decreased his intake of Vitamin K for a period of time, with a higher dose of Warfarin, Sudden Bleeding will occur! In addition, some drugs inhibit cytochrome P450 especially CYP2C9, this leads to the inhibition of metabolism of warfarin which increases the concentration of warfarin in the patient s body and causes bleeding such as.(بابونج) chamomile Another thing that affects the warfarin activity is the replacement of warfarin on albumin, so some drugs may take the place of warfarin on the albumin (warfarin got replaced by another drug), which will increase the concentration of warfarin in the body. Summary of Warfarin Drug Interactions which can be classified into: 1. Pharmacokinetic mechanisms Enzyme induction (increase Warfarin Metabolism): decreased warfarin concentration. Enzyme inhibition (decrease Warfarin Metabolism): increased warfarin concentration. 2. Pharmacodynamic mechanisms Synergism: Give something that impairs Hemostasis, which means increased activity of warfarin (Helping Warfarin), for example drugs that increase catabolism of clotting factors. Competitive antagonism (vitamin K): decreased activity of warfarin, antidote for warfarin. (There is another Antidote to Warfarin which is giving the patient fresh frozen plasma(ffp) because it has clotting factors However this is Not the first choice and this is a clinical antidote, so if you are asked about the main antidote, its Vitamin K) 3. Among the most dangerous are pharmacokinetic interactions with Azapropazone: 8 P a g e
9 P a g e Azapropazone displaces warfarin from plasma protein & inhibits its metabolism Note: The use of a drug that interacts with warfarin is not an absolute contraindication to addition of warfarin; because we can use monitoring to make sure everything is okay. The tables in slides 28 and 29 are not for memorization you can skip this box: The first table mentions the drugs that increase the prothrombin time (drugs that increase the activity of warfarin and anticoagulation effect): The doctor read the drugs that decrease the metabolism of warfarin. He also mentioned thyroid hormones which increase the catabolism of warfarin. He read the drugs that decrease the synthesis of clotting factors. He also read the drugs that have unestablished mechanisms. The second table mentions the drugs that decrease prothrombin time (increase the coagulation effect): He mentioned the drugs that increase synthesis of clotting factors which are vitamin K and estrogen. He read drugs that decrease catabolism of clotting factors. He read drugs that Induce warfarin metabolism. He read drugs that decrease absorption of warfarin. Warfarin toxicity 1. Bleeding: the most dangerous (just like heparin). 2. Warfarin is a teratogenic drug (Classified as an X Drug), it crosses the placenta readily & can cause hemorrhagic disorders & abnormal bone formation in the fetus causing Warfarin Birth Syndrome. Thus, warfarin should never be administered during pregnancy especially in the first three months (6 th - 12 th weeks). The international guide line says that in this case the patient should take daily injections of heparin (but doctors sometimes give her enoxaparin (Clexane) for convenience).
3. Venous thrombosis, due to decreased activity of protein C, that s why we need to use the bridging therapy with heparin and the INR should be between 2-3. If bridging therapy was stopped before reaching the 2-3 safe INR levels (before Warfarin reaches its maximal anti-coagulant effect) Venous thrombosis might occur. 4. Purple toe syndrome (cholesterol microembolization arterial obstruction). Patients that have history of thrombosis take warfarin, so they already have high cholesterol that tend to bind to endothelial cells which forms microthrombi so when the patient takes warfarin, this microthrombi might dissociate from the endothelial layer nearly between the 5 th -10 th week of taking warfarin, which becomes a microemboli, which causes arterial obstruction in the small arterioles, most commonly the small arterioles of the toes that s why it is called Purple toe syndrome. (Note: These cholesterol microemboli don t obstruct pulmonary vessels because these vessels are wider and stronger) Contraindication of warfarin is absolute in pregnancy and it is relative in severe hepatic or renal disease (because there is no warfarin metabolism), vitamin K deficiency, chronic alcoholism and non-steroidal antiinflammatory (NSAIDs) therapy (because of drug-drug interactions; NSAIDs were listed under the category of drugs that increase risk of bleeding in the past tables). Dabigatran (Pradaxa) To prevent the side effects of heparin and warfarin Dabigatran was produced in 2001, it is an expensive drug. Mechanism Of Action (MOA): Direct thrombin inhibitor which inhibits: 1. Both free and fibrin-bound thrombin 10 P a g e
2. Cleavage of fibrinogen to fibrin 3. Thrombin-induced platelet aggregation Note about the Mechanism: Warfarin inhibits the activation of new factors but doesn t do anything to the activated ones, that s why in Warfarin we needed to wait for 5 days until the active factor II is cleared, but here Dabigatran works by directly inhibiting the active thrombin, which means no need to wait for 5 days. Monitoring: We don't need critical monitoring but aptt can be used. Onset of action: 1 hour (Fast), reaches full activity when steady state is reached after 4-5 half lives, delayed by food. Dabigatran doesn t have antidote which is a problem, unlike warfarin if the INR reaches 6-7 we give Vitamin K as an antidote or fresh frozen plasma(ffp) because it has clotting factors or unlike heparin that has an antidote which is protamine sulphate (antibody binds to heparin). This information is Wrong, in the next lecture the Dr mentioned that Dabigatran Has an antidote. Adverse effects: Bleeding (A lot of scientists in the past said that Dabigatran has a higher bleeding risk than Warfarin and Heparin, however recent clinical trials have proved that Dabigatran is not more dangerous than Warfarin and Heparin, in fact they have nearly the same bleeding risk). Dyspepsia So, dabigatran (Pradaxa) is the safest drug, orally active, doesn t need monitoring and doesn t need bridging therapy. 11 P a g e
Rivaroxaban Another drug that was produced to replace warfarin and heparin is Rivaroxaban, it inhibits factor Xa instead of thrombin (factor II). It is expensive, its activity is fast, orally active, doesn t need monitoring, has an antidote and with minor drug-drug interactions like Dabigatran. Equal activity with Dabigatran. It is used with pulmonary embolism and DVT patients. The last problem in the anticoagulants is when the patient get heparin induced thrombocytopenia thrombosis, so what should we do in this case? We mustn t give the patient warfarin because it takes 5 days to be effective and it may cause thrombosis because it reduces protein C and S, so in this case warfarin is totally contraindicated. We have to give the patient a drug that its activity is fast and reduces the thrombosis, we can give Dabigatran or Rivaroxaban but it is an emergency situation and these drugs are given orally, so we have to give an injectable drug which is Argatroban. Argatroban is the drug of choice in heparin induced thrombocytopenia thrombosis, it is an injectable drug and it is factor II (thrombin) inhibitor. Additional Note: Just to know, the known INR definition, which we took in the physio Lab is the following: INR= ( PT of patient Average of PT of 1000 patients in population )ISI (ISI - International Sensitivity Index is usually around 1) (That's why the Dr Didn't focus on it). 12 P a g e
At the end, I want to thank my friend Osama Alzoubi for correcting this sheet and for making it easier to understand and study, it was a great pleasure working with you. For any questions feel free to ask me or Osama and we will do our best to answer them. BEST OF LUCK 13 P a g e