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 headache following a fall has a pink cerebrospinal fluid but the lab reports it xanthochromic. Isn’t xanthochromia supposed to describe yellow discoloration only?

Although xanthochromia literally means yellow color, when it comes to describing the color of the cerebrospinal fluid (CSF), a more liberal—but perhaps misleading— definition of xanthochromia extending to other colors, such as pink and orange, is commonly found in the literature. 1-5

In the presence of red blood cells (RBCs) in the subarachnoid space, as seen in subarachnoid hemorrhage (SAH), 3 pigments are formed by the breakdown of hemoglobin in the CSF: oxyhemoglobin, methemoglobin, and bilirubin. Oxyhemoglobin is typically red but has also been reported to appear orange or orange-yellow with dilution.6  Methemoglobin is brown and bilirubin is yellow. Of these pigments, only bilirubin can be formed solely from in vivo conversion, while oxyhemoglobin and methemoglobin may also form after CSF has been obtained (eg, in tubes).  Due to the suboptimal reliability of visual inspection, some have argued for the routine use of spectrophotometry of the CSF instead in patients with suspected SAH.7

In our patient, the “pink xanthochromia” may be related to RBC breakdown either due to a SAH or as a result of hemolysis in the sample tubes themselves, especially if there was a delay in processing the specimen. Even if he had “true xanthochromia” with yellow discoloration of CSF, make sure to exclude other causes besides SAH, such as high CSF protein, hyperbilirubinemia, rifampin therapy, and high carotenoid intake (eg, carrots).

 

References

  1. Seehusen DA, Reeves MM, Fomin DA. Cerebrospinal fluid analysis. Am Fam Phys 2003;68:1103-8. https://www.aafp.org/afp/2003/0915/p1103.pdf
  2. Edlow JA, Bruner KS, Horowitz GL. Xanthochromia. A survey of laboratory methodology and its clinical implications. Arch Pthol Lab Med 2002;126:413-15.
  3. Lo BM, Quinn SM. Gross xanthochromia on lumbar puncture may not represent an acute subarachnoid hemorrhage. Am J Emerg Med 2009;27:621-23.
  4. Koenig M. Approach to the patient with bloody or pigmented cerebrospinal fluid. In Irani DN, ed, Cerebrospinal fluid in clinical practice. 2009. https://doi.org/10.1016/B978-1-4160-2908-3.X0001-6
  5. Welch H, Hasbun R. Bacterial infections of the central nervous system. In Handbook of Clinical Neurology, 2010. https://www.sciencedirect.com/handbook/handbook-of-clinical-neurology/vol/96/suppl/C
  6. Barrows LJ, Hunter FT, Banker BQ. The nature and clinical significance of pigments in the cerebrospinal fluid. Brain 1955; 58: 59-80. https://www.ncbi.nlm.nih.gov/pubmed/14378450
  7. Cruickshank A, Auld P, Beetham R, et al. Revised national guidelines for analysis of cerebrospinal fluid for bilirubin in suspected subarachnoid haemorrhage. Ann Clin Biochem 2008;45:238-44. https://www.ncbi.nlm.nih.gov/pubmed/18482910

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My patient with headache following a fall has a pink cerebrospinal fluid but the lab reports it xanthochromic. Isn’t xanthochromia supposed to describe yellow discoloration only?

Should rifampin be routinely included in the treatment of staphylococcal infections involving retained prosthetic joints?

Rifampin has excellent penetration of biofilms in vitro (1). According to the Infectious Disease Society of America (IDSA) guidelines, it should be used in combination with another anti-staphylococcal antibiotic in the treatment of staphylococcal prosthetic joint infections for 3-6 months following debridement of a retained prosthesis (level A1 recommendation) (2).

Although a small randomized-controlled trial between ciprofloxacin and ciprofloxacin-rifampin reported a dramatic 100% cure rate in patients treated with the combination regimen (vs 58% with ciprofloxacin alone) (3), its small sample size (n=24) with its high drop-out rate, beg for a larger study comparing a more conventional anti-staphylococcal drug regimen such as a beta-lactam or vancomycin with and without rifampin. In the meantime, be on the alert for rifampin-induced drug resistance, hepatotoxicity, and frequent CYP450 drug interactions (e.g. warfarin) when used in combination with other anti-staphylococcal drugs (1).

 

References

  1. Forrest GN, Tamura K. Rifampin combination therapy for nonmycobacterial infections. Clin Microbiol Rev. 2010;23(1):14-34.
  2. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(1):e1-e25.
  3. Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA. 1998;279(19):1537-1541.

 

Contributed by Sam Slavin, Harvard Medical Student, Boston, MA.

Should rifampin be routinely included in the treatment of staphylococcal infections involving retained prosthetic joints?