My 65 year old patient on chronic warfarin happens to have diffuse tracheobronchial calcification on her chest X-ray. Could warfarin be the culprit?

Absolutely! Although tracheobronchial calcification (TBC) is often found as part of normal aging process in the elderly, especially women, long-term warfarin use has also been implicated as a cause of TBC, even among those with less advanced age (1-4).

In a cohort of patients 60 years of age or older, radiographic evidence of trachea and bronchi calcification was found in 47% of patients on warfarin (mean age 64 years, mean duration of treatment 6 years) compared to 19% of controls (1). A positive correlation between the duration of warfarin therapy and increased levels of calcification was also found.  Fortunately, TBC is a benign finding and has no health consequences.

As for the mechanism for this rather intriguing phenomenon, the inhibition of a vitamin K-dependent protein that prevents calcification of cartilaginous tissue seems to be the most plausible (1). Although we often think of vitamin-K dependent factors in relation to the coagulation cascade, several vitamin K-dependent proteins also play an important role in the inhibition of calcification in soft tissues and blood vessels (eg, matrix Gla protein-MGP) (5,6).

In fact, rats maintained on warfarin undergo calcification of cartilage and elastic connective tissue, while exposure of the fetus to warfarin during pregnancy is associated with calcifications in and around joints, airway and nasal cartilages (4,7). These observations further support a causative role of warfarin in inducing TBC.

 

Bonus Pearl: Did you know that MGP deficiency in humans is known as the Keutel syndrome, a rare autosomal recessive disease characterized by several characteristic physical features, including severe cartilage calcifications and depressed nasal bridge?

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References

  1. Moncada RM, Venta LA, Venta ER, et al. Tracheal and bronchial cartilaginous rings: warfarin sodium-induced calcification. Radiology 1992;184:437-39. https://pubs.rsna.org/doi/10.1148/radiology.184.2.1620843
  2. Thoongsuwan N, Stern EJ. Warfarin-induced tracheobronchial calcification. J thoracic Imaging 2003;18:110-12. https://journals.lww.com/thoracicimaging/Abstract/2003/04000/Warfarin_Induced_Tracheobronchial_Calcification.12.aspx
  3. Nour SA, Nour HA, Mehta J, et al. Tracheobronchial calcification due to warfarin therapy. Am J Respir Crit Care Med 2014;189:e73. https://www.atsjournals.org/doi/full/10.1164/rccm.201305-0975IM
  4. Joshi A, Berdon WE, Ruzal-Shapiro C, et al. CT detection of the tracheobronchial calcification in an 18 year-old on maintenance warfarin sodium therapy. AJR Am J Roentgenol 2000;175:921-22. https://www.ajronline.org/doi/full/10.2214/ajr.175.3.1750921
  5. Wen L, Chen J, Duan L, et al. Vitamin K-dependent proteins involved in bone and cardiovascular health (review). Molecular Medicine Reports 2018;18:3-15. https://www.spandidos-publications.com/mmr/18/1/3/abstract \
  6. Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr 2012; 3:166-173. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648717/pdf/166.pdf

7.      Price PA, Williamson MK, Haba T, et al. Excessive mineralization with growth plate closure in rats on chronic warfarin treatment. Proc Natl Acad Sci  U.S.A 1982;79:7734-8. https://www.ncbi.nlm.nih.gov/pubmed/6984192

My 65 year old patient on chronic warfarin happens to have diffuse tracheobronchial calcification on her chest X-ray. Could warfarin be the culprit?

My elderly patient on anticoagulation for non-valvular atrial fibrillation was admitted for evaluation of a fall. Should I discontinue her anticoagulation long term because of potential for intracranial hemorrhage from future falls?

Although there may always be hesitation in resuming anticoagulation (AC) in patients with non-valvular atrial fibrillation (NVAF) and recent fall(s), the weight of the evidence suggests that most patients are still more likely to benefit from AC than be adversely impacted by intracranial hemorrhage.
An often-quoted systematic review article on the risks and benefits of anti-thrombotic (AC or aspirin) therapy in patients with NVAF at risk estimated that persons taking warfarin must fall 295 times in 1 year for warfarin to not be the optimal therapy for reducing the risk of stroke (1). The authors concluded that “a history of and/or the presence of risk factors for falls should not be considered important factors in the decision whether to offer antithrombotic (especially warfarin) therapy to elderly patients with atrial fibrillation”.
In another study involving older adults with NVAF, although a history of falls or documented high risk of falling was associated with a risk of intracranial hemorrhage, this risk did not differ among patients treated with warfarin, aspirin or no antithrombotic therapy (2).
Ultimately, the decision to prescribe AC in patients with NVAF at risk for falls should be made based on shared decision making with patients and caregivers. However, in the absence of absolute contraindications for AC in these patients (eg, intracranial hemorrhage or neurosurgical procedure with high risk for bleeding within the past 30 days, an intracranial neoplasm or vascular abnormality with high risk of bleeding, recurrent life-threatening gastrointestinal or other bleeding events, and severe bleeding disorders), perceived or actual risk of falls by itself should not automatically exempt a patient from receiving AC in NVAF (3).

 

Although much of the data on the relative risk of bleeding against prevention of strokes has been derived from studies involving warfarin, it is reassuring that the risk of intracranial bleed has been lower than that of warfarin for several newer non-vitamin K antagonist direct oral anticoagulants (NOACs or DOACs),  including dabigatran, rivaroxaban, edoxaban and apixaban (4). 

 

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References

1. Man-Son-Hing M, Nichol G, Lau A, et al. Choosing antithrombotic therapy for elderly patiets with atrial fibrillation who are at risk for falls. Arch Intern Med 1999;159:677-685.
2. Gage BF, Birman-Deych E, Kerzner R, et al. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med 2005;118:612-617.
3. Hagerty T, Rich MW. Fall risk and anticoagulation for atrial fibrillation in the elderly: a delicate balance. Clev Clin J 2017;84:35-40.

4. Lopez RD, Guimaraes PO, Kolls BJ, et al. Intracranial hemorrhage in patietns with atrial fibrillation receiving anticoagulation therapy. Blood 2017;129:2980-87. 

My elderly patient on anticoagulation for non-valvular atrial fibrillation was admitted for evaluation of a fall. Should I discontinue her anticoagulation long term because of potential for intracranial hemorrhage from future falls?

Despite taking higher doses of warfarin, my patient’s INR won’t budge. What am I missing?

Poor compliance is probably the most common and least “exciting” explanation for low INRs despite seemingly adequate or high warfarin doses.  Otherwise, consider the following: 

Increased vitamin K intake: Since warfarin acts by inhibiting vitamin K recycling by VKORC1 (Vitamin K epOxide Reductase Complex), find out if your patient takes multivitamins or loves foods or products rich in vitamin K, ranging from leafy green vegetables to nutritional supplements( eg, Ensure) and even chewing tobacco!1 

Drug interactions: Warfarin is notorious for interacting with many drugs, although its effect is more often enhanced than counteracted. Run the patient’s med list and look for “counteractors” of warfarin,  including carbamazepine, phenobarbital, phenytoin, rifampin, and dexamethasone.2 

Hypothyroidism: Thyroid hormone seems to be necessary for efficient clearance of the vitamin K-dependent clotting factors (II, VII, IX, and X). Thus, larger doses of warfarin may be needed when patients are hypothyroid.3 

Hyperlipidemia and obesity: High lipid levels may allow for high vitamin K levels (since it’s lipid-soluble and carried in VLDL), especially at the start of therapy.4,5 

What if the INR is falsely low? This is usually not the problem although one major trial took a lot of heat for using a point of care INR device that gave low readings in anemic patients.6  When in doubt, check a chromogenic factor Xa test to confirm; 20-30% activity correlates with a true INR of 2-3.7

If none of these explanations fit the bill, consider genetic testing for warfarin resistance.8,9

Bonus Pearl: Did you know that use of warfarin (introduced in 1948 as a rodenticide) has already led to some selective pressure for VKORC1 mutations in exposed rat populations.10

References

  1. Kuykendall JR, et al. Possible warfarin failure due to interaction with smokeless tobacco. Ann Pharmacother. 2004 Apr;38(4):595-7. https://www.ncbi.nlm.nih.gov/pubmed/14766993
  2. Zhou SF, et al. Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. https://www.ncbi.nlm.nih.gov/pubmed/19515014
  3. Bucerius J, et al. Impact of short-term hypothyroidism on systemic anticoagulation in patients with thyroid cancer and coumarin therapy. Thyroid. 2006 Apr;16(4):369-74. https://www.ncbi.nlm.nih.gov/pubmed/16646683
  4. Robinson A, et al. Lipids and warfarin requirements. Thromb Haemost. 1990;63:148–149. https://www.ncbi.nlm.nih.gov/pubmed/16646683
  5. Wallace JL, et al. Comparison of initial warfarin response in obese patients versus non-obese patients. J Thromb Thrombolysis. 2013 Jul;36(1):96-101. https://www.ncbi.nlm.nih.gov/pubmed/23015280
  6. Cohen D. Rivaroxaban: can we trust the evidence? BMJ 2016;352:i575. https://www.bmj.com/content/352/bmj.i575/rapid-responses
  7. Sanfelippo MJ, et al. Use of Chromogenic Assay of Factor X to Accept or Reject INR Results in Warfarin Treated Patients. Clin Med Res. 2009 Sep; 7(3): 103–105. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757431/
  8. Rost S, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004;427:537–41. https://www.ncbi.nlm.nih.gov/pubmed/14765194
  9. Schwarz UI, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008 Mar 6;358(10):999-1008. https://www.ncbi.nlm.nih.gov/pubmed/18322281
  10. Rost S, et al. Novel mutations in the VKORC1 gene of wild rats and mice–a response to 50 years of selection pressure by warfarin? BMC Genet. 2009 Feb 6;10:4. https://bmcgenet.biomedcentral.com/articles/10.1186/1471-2156-10-4

Contributed by Nicholas B Bodnar, Harvard Medical School student, Boston, MA.

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Despite taking higher doses of warfarin, my patient’s INR won’t budge. What am I missing?

My elderly patient on chronic warfarin with recent hospitalization for soft tissue infection is now readmitted with gastrointestinal bleed and a newly-discovered supra-therapeutic INR? Why did her INR jump?

Assuming no recent changes in the dose of warfarin, one potential culprit may be her recent antibiotic exposure. Of the long list of antibiotics associated with elevated INR, quinolones (e.g. ciprofloxacin, levofloxacin), trimethoprim-sulfamethoxazole, macrolides (e.g. azithromycin), and azole antifungals (e.g. fluconazole) are generally thought to carry the highest risk of warfarin toxicity, while amoxacillin and cephalexin may be associated with a more modest risk. 1-3

Other drugs such as amiodarone (Did she have atrial fibrillation during her recent hospitalization?), acetaminophen (Has she been receiving at least 2 g/day for several consecutive days?), and increasing dose of levothyroxine (Was she thought to be hypothyroid recently?) should also be considered.3,4

Also remember to ask about herbal supplements (eg, boldo-fenugreek, dong quai, danshen) that may potentiate the effect of warfarin. 3 Of course, poor nutrition in the setting of recent illness might have also played a role.5

As far as the mechanisms for drug interaction with warfarin, some drugs act as cytochrome p450 inhibitors (thus reducing the metabolism of warfarin), while others influence the pharmacodynamics of warfarin by inhibiting the synthesis or increasing the clearance of vitamin K-2 dependent coagulation factors.3

Antibiotics may increase the risk of major bleeding through disruption of intestinal flora that synthesize vitamin K-2 with or without interference with the metabolism of warfarin through cytochrome p450 isozymes inhibition.

Check out a related pearl on P4P: https://pearls4peers.com/2015/06/25/is-there-anyway-to-predict-a-significant-rise-in-inr-from-antibiotic-use-in-patients-who-are-also-on-warfarin  

 

References

  1. Baillargeon J, Holmes HM, Lin Y, et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012 February ; 125(2): 183–189. https://www.ncbi.nlm.nih.gov/pubmed/22269622
  2. Juurlink DN. Drug interactions with warfarin: what every physician should know. CMAJ, 2007;177: 369-371. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1942100/pdf/20070814s00018p369.pdf
  3. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S-e88S. doi:10.1378/chest.11-2292.  https://www.ncbi.nlm.nih.gov/pubmed/22315269
  4. Hughes GJ, Patel PN, Saxena N. Effect of acetaminophen on international normalized ratio in patients receiving warfarin therapy. Pharmacotherapy 2011;31:591-7. https://www.ncbi.nlm.nih.gov/pubmed/21923443
  5. Kumar S, Gupta D, Rau SS. Supratherapeutic international normalized ratio: an indicator of chronic malnutrition due to severely debilitating gastrointestinal disease. Clin Pract. 2011;1:e21. doi:10.4081/cp.2011.e21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981245

 

Contributed by Rachel Weitzman, Medical Student, Harvard Medical School, Boston, MA.

My elderly patient on chronic warfarin with recent hospitalization for soft tissue infection is now readmitted with gastrointestinal bleed and a newly-discovered supra-therapeutic INR? Why did her INR jump?

Is there anyway to predict a significant rise in INR from antibiotic use in patients who are also on warfarin?

Not really!  Many of the commonly used antibiotics have the potential for increasing the risk of major bleeding through disruption of intestinal flora that synthesize vitamin K-2 with or without interference with the metabolism of warfarin through cytochrome p450 isozymes inhibition.

Although there may be some inconsistencies in the reports, generally quinolones (e.g. ciprofloxacin, levofloxacin), sulonamides (e.g. trimethoprim-sulfamethoxazole), macrolides  (e.g. azithromycin), and azole antifungals (e.g. fluconazole) are thought to carry the highest risk of warfarin toxicity, while amoxacillin and cephalexin may be associated with a more modest risk (1,2).  Metronidazole can also be a culprit (2).

References

1. Baillargeon J, Holmes HM, Lin Y, et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012 February ; 125(2): 183–189. https://www.ncbi.nlm.nih.gov/pubmed/22269622

2. Juurlink DN. Drug interactions with warfarin: what every physician should know. CMAJ, 2007;177: 369-371. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1942100/pdf/20070814s00018p369.pdf

Is there anyway to predict a significant rise in INR from antibiotic use in patients who are also on warfarin?