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 patient with no known liver disease appears to have bilateral asterixis. What other causes should I consider?

Although originally described in 1949 in patients with liver disease and labelled as “liver flap”, numerous other causes of asterixis exist aside from severe liver disease (1,2). As early as 1950s, asterixis was observed among some patients with heart failure and pulmonary insufficiency but without known significant liver disease (3). Azotemia has also been associated with asterixis.

 
Don’t forget about medication-associated asterixis . Commonly used drugs such as gabapentin, pregabalin, phenytoin, and metoclopramide have been associated with asterixis (1,4) . Even antibiotics such as ceftazidime and high dose trimethoprim-sulfamethoxazole may be culprits (1,5). There are many psychiatric drugs including lithium, carbamazepine, clozapine, and valproic acid that have been implicated (1,6) as well. Some reviews have also included hypomagnesemia and hypokalemia on the list of causes of asterixis (1).

 
Although asterixis is essentially a negative myoclonus with episodic loss of electrical activity of muscle and its tone, its exact pathophysiology remains unclear (7). 

 

Bonus Pearl: Did you know that the origin of the word asterixis is An (negative)-iso (equal)-sterixis (solidity) which was shortened by Foley and Adams, its original discoverers, to what we now refer to as “asterixis” (1).

 

References
1. Agarwal R, Baid R. Asterixis. J Postgrad Med 1016;62:115-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944342/ 2. Pal G, Lin MM, Laureno R. Asterixis: a study of 103 patients. Metab Brain Dis; 2014:29:813-24. https://link.springer.com/article/10.1007%2Fs11011-014-9514-7
3. Conn HO. Aterixis—Its occurrence in chronic pulmonary disease, with a commentary on its general mechanism. N Engl J Med 1958;259:564-569. https://www.nejm.org/doi/full/10.1056/NEJM195809182591203
4. Kim JB, Jung JM, Park MH. Negative myoclonus induced by gabapentin and pregabalin: a case series and systemic literature review. J Neurol Sci 2017;382:36-9. https://www.sciencedirect.com/science/article/pii/S096758681830225X
5. Gray DA, Foo D. Reversible myoclonus, asterixis, and tremor associated with high dose trimethoprim-sulfamethoxazole: a case report. J Spinal Cord Med 2016; Vol. 39 (1), pp. 115-7. https://www.ncbi.nlm.nih.gov/pubmed/26111222
6. Nayak R, Pandurangi A, Bhogale G, et al. Aterixis (flapping tremors) as an outcome of complex psychotropic drug interaction. J Neuropsychiatry Clin Neurosci 2012;24: E26-7. https://neuro.psychiatryonline.org/doi/pdf/10.1176/appi.neuropsych.101102667. Ugawa Y, Shimpo T, Mannen T. Physiological analysis of asterixis: silent period locked averaging. J Neurol Neurosurg Psych 1989;52:89-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1032663/pdf/jnnpsyc00523-0104.pdf

 

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My patient with no known liver disease appears to have bilateral asterixis. What other causes should I consider?