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Non-bleeding Complications of Warfarin Therapy – Opposing Views & the Need for a Registry

Henry I. Bussey, Pharm.D., FCCP, FAHA
Alex C Spyropoulos, MD, FACP, FCCP
October, 2007

Henry I. Bussey, Pharm.D., FCCP, FAHA: Dr. Spyropoulos and I recently realized that we have somewhat conflicting views on the frequency of some of the non-bleeding adverse effects of warfarin. I maintain that warfarin, if managed well to minimize the bleeding complications, is almost without adverse effects. Although there are several recognized and proposed adverse effects with warfarin, my perception is that these are rarely seen. I also realize, however, that basing conclusions on one's perceptions can be very misleading. How many of us have talked to orthopedic surgeons who are confident that their patients are not at risk for a symptomatic DVT much less a PE? As I understand the "rule of 3s", if the "true" incidence of a given adverse event is 1 in 1,000, I would have to actually evaluate at least 3,000 patients in order to be 95% confident of identifying one patient with the adverse event in question. Consequently, my experience of "following" a few hundred patients annually and not recalling a high number of non-bleeding complications could leave me with a false conclusion that these adverse effects are more rare than they actually are. Even so, I will summarize my perceived experience below, invite Dr. Spyropoulos to present his (likely opposing) views, and we both invite others to contribute their perspectives on these issues as well as voice their opinions on the value of having ClotCare create a registry for documenting such adverse events. As always, comments may be sent to Marie Walker at webmaster@clotcare.com.

Allergy: I suspect that allergy is probably the most common non-bleeding adverse event attributed to warfarin. However, I'm not sure that I saw a single case during my 10 years of managing a clinic of about 300 to 500 patients in the University clinics here in San Antonio. Because we were an outpatient referral service, could it be that those with allergic responses were identified before being referred to our clinic? Could it be that our largely Hispanic population is less susceptible to warfarin allergy?

Approximately 12 years ago when I teamed up with Roger Lyons, MD to establish an anticoagulation service in the private sector, I started following perhaps a half-dozen of Dr. Lyons' patients who were on anisindione (brand name Miradon) after developing a rash on warfarin. These patients tolerated anisindione well for an extended period of time. Later, however, when the anisindione became unavailable in the U.S., we were faced with discontinuing anticoagulation, switching the patient to low molecular weight heparin (LMWH), or trying warfarin again. In several instances, when we switched the patient back to warfarin, the patient tolerated the drug well without an allergic response. Based on the premise that allergic responses to warfarin may be due to the dye used to color the tablet rather than the drug itself, we typically had patients resume warfarin with the 10 mg (dye-free) warfarin tablet. Only an occasional patient required LMWH.

Based on the above experience, my perception is that allergic response to warfarin is quite infrequent and in most cases is probably due to something other than the drug itself. Having said that, it is somewhat ironic that earlier this week in one half-day clinic, I saw two patients new to warfarin who had developed a rash. In one, the rash was very limited and apparently confined to the forearms. In the second patient, the rash was more severe and rather diffuse over the trunk. However, that patient also had been started on LMWH and diltiazem at the same time the warfarin was started. His cardiologist had discontinued the diltiazem the morning of our visit and started the patient on an oral steroid regimen. In addition, his INR was at a point at which we were able to discontinue his LMWH. We elected to continue the warfarin in order to better assess the role of diltiazem or LMWH in this reaction, but will consider changing to the 10 mg warfarin tablet if the rash persists.

Skin necrosis: I am confident (and thankful) that I have seen only one or two cases of warfarin-induced skin necrosis in the last 20+ years. Perhaps the low frequency of such reactions is due to a greater appreciation for the potential for this problem, especially in those with (or who are suspected of having) a hypercoagulable state and the realization that such patients need to be adequately treated with LMWH or a similar agent before the warfarin is started. Warfarin-induced skin necrosis is thought to be due to a hypercoagulable state induced by the rapid fall in Protein C and/or Protein S during the initiation phase of warfarin therapy.

Blue toe syndrome: This condition is thought to be due to small cholesterol emboli obstructing small vessels in the skin in the involved area. Again, I can recall seeing only 1 or 2 such patients in 20+ years of practice; but I must also confess that the name (which is something of a misnomer) may have resulted in my missing this condition in some patients. "Blue toe syndrome" does not just affect the toe(s); although some descriptions I have read suggest that it characteristically affects the great toe. In reality, there are reports of "blue toe syndrome" affecting various parts of the foot including the entire plantar surface. I recall one bypass surgery patient from years ago who continued to have pain and dark discoloration of the ball of his foot, which we tended to attribute to poor peripheral circulation. In retrospect, perhaps he too had blue toe syndrome with the plantar surface of his feet being more affected than his toes were.

Black ("furry") tongue: I have never seen this condition. However, I do recall a fellow Pharm.D. resident that encountered such a patient in the anticoagulation clinic at our VA hospital system some 30 years ago.

Limb gangrene: Again, this is a condition which I have not seen personally; but perhaps my not having seen a case is related to the fact that my practice is entirely outpatient based. In my mind, I think of this as a "super" case of warfarin-induced skin necrosis. The reports that I've read regarding this condition occurred when patients with (unrecognized?) heparin-induced thrombocytopenia (which is characteristically associated with tremendous level of thrombin generation) were given large doses of warfarin. A substantial prolongation in the INR in these patients was taken as an indication that Protein C and Protein S (due to their short half-lives) had also declined substantially thereby tipping the balance even more toward a prothrombotic state (with the excessive production of thrombin being present). Again, I'm hopeful that clinician awareness of the circumstances that can lead to such a catastrophic complication will reduce the likelihood of this adverse effect occurring in the future.

Osteoporosis: Although international experts have openly voiced their view that there are not good data to support osteoporosis as a complication of warfarin therapy, others have reported an increase in fracture rates among patients taking warfarin and pointed out that there is a biochemically plausible mechanism to explain warfarin having such an effect (http://www.clotcare.com/clotcare/warfarinfracturerisk.aspx). However, because these data came from a registry of patients with atrial fibrillation, it also is possible that the increased fracture rate may have been due to other causes; such as an increased rate of falls in patients with symptomatic atrial fibrillation. Even so, it also has been suggested that if warfarin does interfere with bone metabolism, it is probable that low dose vitamin K supplementation may obviate this effect while helping to stabilize the INR.

Hair loss: My impression is that hair loss is a fairly common complaint but that it is not related to warfarin therapy. I discussed this issue with a dermatologist/faculty member at the University of Texas Health Science Center at San Antonio who was doing research in hair loss (see http://www.clotcare.com/clotcare/faq_warfarinhairloss.aspx). This individual, after reviewing the data, had concluded that the hair loss in most such cases was most likely due to the condition for which the warfarin was being used. He pointed out that any major stress (such as a stroke, PE, DVT, bypass surgery, etc.) can result in hair loss but that such hair loss is typically delayed. Therefore, he proposed the scenario in which the patient underwent a stressful event, was treated with anticoagulation, and then some days to weeks later while taking warfarin noted hair loss. Since warfarin was the current medication at the time the hair loss was identified, the patient tended to blame the warfarin rather than the preceding stress.

Feeling cold: From discussions with colleagues, this too seems to be a fairly common complaint of patients. My initial presumption is that this is likely a psychosomatic complaint based on the perception that warfarin is a "blood thinner" and since the blood is thinner, they feel cold. I would also suspect that in some cases, peripheral vascular disease, heart failure, anemia, and perhaps other potential causes of compromised circulation could lead to a feeling of coolness in the extremities. Could there be a cause and effect relationship with warfarin therapy? That may be an interesting question to explore further.


Alex C Spyropoulos, MD, FACP, FCCP: A few months ago, the founder of ClotCare (Henry Bussey, PharmD, FCCP) and I became involved in a small debate on whether non-hematological complications of warfarin therapy occurred in greater number than was discussed in the literature. As such, I'm presenting my view of things with this small editorial. As I am fortunate enough to be a Medical Director of a rather large (~4000 patient) Anticoagulation Clinic, I have noted that warfarin intolerance syndromes occur more often than the isolated case series or reports noted in the literature. I have not included other syndromes for the purposes of this debate, including the well-described warfarin failure and warfarin resistance syndromes that can not be considered a "complication" of warfarin per se.

Warfarin intolerance usually can take the form of true warfarin hypersensitivity reactions in the form of maculopapular reactions, warfarin-induced skin necrosis, or purple- or blue-toe syndrome. Although the histopathological mechanisms of these forms are different, the end result in terms of long-term anticoagulant therapy is nearly always the same – these patients will likely need alternate anticoagulants. Alternate anticoagulants as oral agents previously most often involved non-coumarin derivatives such as anisindiones or the possibility of the oral direct thrombin inhibitor ximelagatran in countries where it was approved. Unfortunately, both agents are no longer available, as anisindione derivatives are not being commercially produced and ximelagatran was taken off the world market in February 2006 due to continuing safety concerns with respect to hepatotoxicity. What remain are essentially parenteral anticoagulants such as low molecular weight heparin or the pentassaccharide fondaparinux for treatment in these patients.

That these 3 conditions are more common than we are led to believe simply, in my experience, comes from the fact that – in a large, centralized referral anticoagulation clinic such as ours - we have approximately 36 patients on long-term parenteral anticoagulant agents due to warfarin intolerance, which roughly represents .01% or 1 in 1000, of the patient population in our clinic. Though this does constitute an uncommon phenomenon, it is by no means a "rare" one, as previously suggested. Indeed, a similar paradigm has shown that perhaps the incidence of heparin-associated elevation of transaminases, including the possibility of hepatic injury, has not been as trivial as we thought when we look at the heparin arms of large clinical studies comparing newer antithrombotic agents with standard anticoagulants.

In my view, this issue can be looked at more thoroughly with establishment of a registry, perhaps through an organization like ClotCare or the Anticoagulation Forum, to assess a more reasonable estimate of the prevalence of warfarin intolerance syndromes.

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Sunday, November 23, 2014