What are the causes of an elevated International Normalized Ratio (INR)?

From the Guidelines

Elevated INR values should be managed promptly to prevent bleeding complications, with the approach depending on the severity of the elevation and the presence of bleeding, according to the American Heart Association/American College of Cardiology Foundation guide to warfarin therapy 1. When managing elevated INR, it's crucial to consider the risk of bleeding, which increases significantly when the INR exceeds 4 and rises sharply with values above 5. The management strategies include stopping warfarin, administering vitamin K1, or infusing fresh plasma or prothrombin concentrate.

• For mild elevations (INR 3-5 with no bleeding), skipping one or more doses of warfarin until the INR returns to the target range (typically 2-3 for most conditions) may be recommended.
• For moderate elevations (INR 5-9), skipping 1-2 doses of warfarin and administering oral vitamin K (1-2.5 mg) can effectively lower the INR without causing resistance to warfarin once it is resumed 1.
• For severe elevations (INR >9) or if bleeding is present, immediate medical attention is necessary, potentially requiring intravenous vitamin K, fresh frozen plasma, or prothrombin complex concentrate, as outlined by the American College of Chest Physicians 1. Regular INR monitoring is essential after any intervention until stable values are achieved, as the risk of bleeding remains a concern until the INR is within the therapeutic range. Key factors that can contribute to an elevated INR include medication interactions, dietary changes (especially foods high in vitamin K), alcohol consumption, liver disease, or certain illnesses, all of which can intensify the anticoagulant effect of warfarin, leading to excessive anticoagulation and increased bleeding risk 1.

From the FDA Drug Label

The following factors, alone or in combination, may be responsible for INCREASED PT/INR response: ENDOGENOUS FACTORS: blood dyscrasias — diarrhea hyperthyroidism see CONTRAINDICATIONS elevated temperature poor nutritional state cancer hepatic disorders steatorrhea collagen vascular disease infectious hepatitis vitamin K deficiency congestive heart failure jaundice EXOGENOUS FACTORS: Potential drug interactions with warfarin sodium tablets are listed below by drug class and by specific drugs. Classes of Drug also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations

• Increased and decreased PT/INR responses have been reported (oral) (17-Alkyl Penicillins, intravenous, Gout Treatment Agents Testosterone Derivatives) (fluoroquinolones) (topical) ogen dextran (intravaginal, oral, systemic) activator (t-PA) dextrothyroxine moricizine hydrochloride* tolbutamide diazoxide nalidixic acid tramadol diclofenac naproxen trimethoprim/sulfamethoxazole dicumarol neomycin urokinase diflunisal norfloxacin valdecoxib disulfiram ofloxacin valproate doxycycline olsalazine vitamin E erythromycin omeprazole zafirlukast esomeprazole oxandrolone zileuton ethacrynic acid oxaprozin ezetimibe oxymetholone fenofibrate pantoprazole

The factors that may be responsible for an elevated INR include various endogenous factors such as blood dyscrasias, diarrhea, hyperthyroidism, and vitamin K deficiency, as well as exogenous factors like certain medications, dietary deficiencies, and prolonged hot weather 2.

• Key factors that may increase the risk of elevated INR include:
  • Certain medications, such as fluoroquinolones, diclofenac, and trimethoprim/sulfamethoxazole
  • Dietary deficiencies, such as a low intake of vitamin K
  • Prolonged hot weather
  • Unreliable PT/INR determinations It is essential to monitor the patient's PT/INR response closely when initiating or discontinuing any of these factors, as the net effect of warfarin on PT/INR response may be unpredictable 2.

From the Research

Elevated INR: Management and Treatment

• Elevated INR is a common problem with warfarin therapy and can lead to major or life-threatening bleeding 3, 4, 5.
• The goal of urgent warfarin reversal is to elevate or replace vitamin K-dependent clotting factors 5.
• Treatment options include the combination of vitamin K and coagulation factor replacement with either prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP) 4, 6.

Prothrombin Complex Concentrates (PCCs) vs Fresh Frozen Plasma (FFP)

• PCCs offer a rapid and specific method for replacing vitamin K-dependent clotting factors and restoring normal hemostasis in the context of over-coagulation 5.
• PCC use is associated with a significant reduction in all-cause mortality compared to FFP 6.
• PCC use is more likely to achieve normalization of international normalized ratio (INR) and results in a shorter time to INR correction 6.
• Patients receiving PCC have a lower risk of post-transfusion volume overload compared to FFP 6.

Activated Prothrombin Complex Concentrate (aPCC) for Warfarin Reversal

• aPCC is safe and effective at reversing the effects of warfarin in patients with traumatic intracranial hemorrhage (TIH) 7.
• Fixed, low-dose aPCC is more effective at reversing the effects of warfarin than FFP in patients with TIH 7.
• The median time to reversal is significantly shorter in the aPCC group compared with the FFP group 7.

Monitoring and Adjusting Warfarin Dose

• The INR should be monitored frequently (eg, 2 to 4 times per week) immediately after initiation of warfarin 3.
• Adjusting a steady-state warfarin dose depends on the measured INR values and clinical factors 3.
• Patients who have an elevated INR will need more frequent testing and may also require vitamin K1 3.