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Anticoagulation Overview - 12/10/2012

posted Dec 10, 2012, 11:25 AM by Rohit Das   [ updated Dec 27, 2012, 6:38 AM by Purnema Madahar ]
Hepain, heparin, heparin…almost all our patients get it for one reason another, and today at M&M, we appreciated the potential adverse effects of it and other anticoagulants – BLEEDING. I thought I would take some time today to give an overview of some the most common anticoagulant medications we use, commenting on their mechanisms, monitoring, adverse effects, other important clinical factoids, etc… 

Unfractionated Heparin (UFH)

·         Heparin was first discovered in 1916 by a second year medical student at Johns Hopkins. It is a naturally occurring anticoagulant produced mainly in basophils in mast cells. Currently, most of it is manufactured via the intestinal cells of…pigs!!

·         Unfractionated heparin is a fairly large, sulfated polysaccharide. In current formulations, the molecular weight of unfractionated chains ranges from 5,000 to 30,000 units, with an average of 15,000 units (this becomes important later…).

·         Heparin activates antithrombin via a unique pentasaccharide sequence. The reason unfractionated heparin is called “unfractionated” is that one-third of the heparin chains in current formulations do not have this sequence, and thus have little to no anticoagulant activity. Upon binding, heparin induces a conformational change in the reactive center of antithrombin, which enhances the rate at which antithrombin inhibits factor XA by about two-fold. Heparin molecules that have a molecular weight greater than 5400 units are also able to bridge thrombin and antithrombin together, stabilizing an inhibitory complex. Thus, heparin is able to anticoagulate by two, antithrombin dependent, mechanisms.

·         The dosing of UFH, as the glorious red book delineates, needs to be monitored and adjusted constantly. This is because heparin binds to a bunch of other plasma proteins that decrease the anticoagulant activity of heparin. This varies from patient to patient, as acute phase reactants avidly bind heparin, and their relative amount is dependent on severity of illness. Thus, we have to check aPTT every six…stupid…hours…annoying.

·         But even that isn’t good enough!! Twenty-five percent of patients are “heparin-resistant,” which is defined as requiring ≥ 35,000 units/day. However, certain acute-phase proteins, like fibrinogen and factor VIII, shorten the aPTT, but have no effect on anti-factor XA levels. Thus, measuring the latter can be of utility in patients deemed to be “heparin-resistant.”

·         Adverse effects are significant. Obviously, bleeding is the most common one, the incidence of which increases with higher dosing. The relatively short half-life of heparin (mean of 1-2 hours) and reversibility with protamine make this a manageable complication. Heparin induced-thrombocytopenia (HIT) is also relatively common, occurring in 1-3% of patients receiving porcine heparin for 7-14 days. Not going to delve too much into HIT, but the thrombotic complications, particularly arterial, can be life-threatening. Additionally, if given for > 1 month, heparin can lead to osteoporosis. Finally, heparin can lead to modest elevations of transaminase levels, which usually isn’t a big deal other than leading to unnecessary Liver consults.

Low Molecular Weight Heparin (LMWH)

·         Not to go into too many details, but the research around LMWH first started in the 1970s, and clinical trials began in the late 1980s. In May of 1998, the FDA first approved Enoxaparin for in and out-patient treatment of venousthromboembolic disease.

·         By controlled enzymatic degradation, LMWH is created from UFH, leading to a uniformly smaller molecule (molecular weight of 4500-5000). Its anticoagulant activity is mostly from potentiation of antithrombin inhibition of factor XA, as the majority of chains in LMWH preparations are too small to bridge and stabilize a thrombin-antithrombin complex.

·         LMWH does not bind other heparin-binding proteins as avidly as UFH, and thus has a longer half-life (about 4-7 hours) and a more predictable anticoagulant response (and thus doesn’t need to be monitored typically). It is cleared by the kidney, so beware utilizing this drug in patients with chronic kidney disease (need lower dosing, and monitoring in certain circumstances). Dosing is based on weight, and studies looking at obesity and LMWH pharmacokinetics have NOT led to recommendations for capped dosing, but as we learned today, this is a very controversial subject.

·         There is a significant amount of data supporting LMWH over UFH for various indications, including prevention/treatment of VTE disease (especially in patients with malignancies – CLOT trial) and acute coronary syndrome (ESSENCE trial, among others).

·         Regarding adverse effects; bleeding remains the most important issue. Importantly, protamine is not as effective as an antidote for LMWH as compared to UFH. Protamine only binds large heparin chains, thus completely reversing thrombin inhibition by antithrombin via the minority of LMWH chains that are sufficiently large enough to stabilize the thrombin-antithrombin complex. Since protamine does not bind the majority of smaller, LMWH chains, it only partially effects the antithrombin mediated inhibition of factor XA…I hope all that made sense. Additionally, LMWH has overall lower incidence of osteoporosis, and most importantly, HIT (4-5 fold decrease).


·         The first inklings of warfarin arose from the discovery of a toxic substance in spoiled hay which led to a sporadic, hemorrhagic illness in cows in the northern U.S. and Canada. In 1940, the substance was identified as dicoumarol, a metabolite of coumarin, a substance present in many plants, particularly sweet grass and woodruff. Subsequent pharmaceutical efforts to create potent rat poisons based on dicoumarol led to the creation of warfarin in 1948. In 1951, after a U.S. army inductee killed himself ingesting warfarin, clinical studies utilizing it as a therapeutic anticoagulant began. THAT is a CRAZY story.

·         Warfarin works by directly inhibiting vitamin K-epoxide reductase (VKOR), thus decreasing the synthesis of vitamin K dependent clotting proteins (II, VII, IX and X) and some anticoagulant proteins (C and S). The mechanism is a bit complicated; all the clotting proteins are rendered active by post-translational carboxylation of their N-terminus. The enzyme that catalyzes this is dependent on reduced vitamin K (Vit K-hydroquinone). Upon carboxylation, oxidized vitamin K is released (Vit K epoxide), then recycled to its reduced form by VKOR – SO, warfarin inhibits this recycling process…

·         Why do we often “bridge” to warfarin for high-risk conditions? Well, there are a couple of reasons. First of all, initially, active protein C and S levels drop before the clotting proteins, making warfarin a bit pro-thrombotic early on (and can lead to skin necrosis in C/S deficient patients, see below). Secondly, since factor X and II have long half-lives (24 and 72 hours respectively) it takes time for the inactive forms of the clotting proteins to replace the previously active forms.

·         Warfarin metabolism is affected by SO MANY things. CYP2C9 (mode of hepatic clearance) variant alleles lead to altered, but overall decreased, metabolism of warfarin and difficulty in maintaining an appropriate dose. VKOR polymorphisms also variably effect warfarin dosing. Drugs also have a significant effect, one way or the other. Antibiotics PPIs, amiodarone, statins/fibrates et. al. pose a risk for overanticoagulation, whereas drugs like rifampin increase warfarin metabolism.  Diet, with variable vitamin K content, and even smoking (based on recent meta-analyses) also impact warfarin metabolism. Taken all together – frequent, annoying, INR monitoring.

·         Important adverse effects include bleeding and congenital abnormalities – don’t give it to pregnant patients. A rare complication is skin necrosis, which occurs mainly in patients with protein C and S deficiencies. In such patients, precipitously falling levels of protein C and S via warfarin (see above) lead to thrombosis; it’s not clear why this thrombosis localizes to the microvasculature of fatty tissue, though.

·         The inconvenience of Warfarin, in part, led to the FDA ultimately approving another oral anticoagulant, Dabigatran (a thrombin inhibitor) for nonvalvular atrial fibrillation. In that study (attached), which was designed for non-inferiority, a dose of 150mg BID was not only non-inferior, but superior to warfarin in reduction of ischemic/hemorrhagic stroke. Furthermore, the rates of bleeding were similar (though the study did show an increased rate of bleeding with Dabigatran in patients older than 75 years old).

Dabigatran versus Warfarin in Patients with Atrial Fibrillation

Connolly et. al., NEJM 2009, Volume 361 (12): 1139-1151

I think that’s enough for today…though had a lot of fun writing this one actually. By the way, a lot of the information I wrote about today comes from textbooks viewed via MD-Consult, a resource on the intranet that I hope you guys are utilizing…till next time…