A mechanical mitral valve, a dental infection and an INR of 6.8

Which warfarin is being handled Warfarin is a racemate. S-warfarin carries roughly three to five times the anticoagulant potency of R-warfarin and is cleared almost entirely by CYP2C9; R-warfarin is handled by CYP1A2 and CYP3A4. Anything that blocks CYP2C9 therefore produces a disproportionate rise in INR.

What co-trimoxazole does

• Sulfamethoxazole is a potent inhibitor of CYP2C9 (with weaker effects on CYP2C19); trimethoprim inhibits CYP2C8 and contributes.
• Reduced S-warfarin clearance leads to accumulation of the active enantiomer, so the same 5 mg dose now produces a much larger anticoagulant effect.
• Both components are also highly protein-bound and can displace warfarin, though this is a transient and minor contributor compared with enzyme inhibition.
• Broad-spectrum suppression of gut flora reduces bacterial vitamin K2 synthesis, lowering the supply of reduced vitamin K for gamma-carboxylation of factors II, VII, IX and X.

Why day five Enzyme inhibition begins within 24-48 hours, but the INR only reflects it once the longer-lived factors (especially prothrombin) fall. Peak effect at three to seven days is exactly the pattern in this man, which supports the interaction rather than an unrelated bleed.

Other contributors to consider The acute infection itself, reduced oral intake of vitamin K-rich foods, and any paracetamol or NSAID taken for dental pain. Note that enzyme induction would have lowered the INR over one to two weeks, which is the opposite of what happened. Host genetics (CYP2C9 *2/*3 alleles, VKORC1) would have amplified the effect. This was a predictable, preventable interaction.

First, grade the bleeding He has mucosal bleeding (gums), haematuria and bruising, a haemoglobin fall of 1.5 g/dL, but he is normotensive, not tachycardic, has no haematemesis or melaena and no neurological signs. That is minor/mucosal bleeding with a supratherapeutic INR, not major or life-threatening bleeding. Management differs sharply between the two.

Actions

1. Stop warfarin.
2. Give phytomenadione (vitamin K1) 1-2.5 mg orally. Oral is as effective as intravenous in a patient who is not actively bleeding to death and avoids the small risk of anaphylactoid reaction; use 0.5-1 mg slow IV only if he cannot swallow or absorb. Do not give 10 mg IV: large doses cause prolonged warfarin resistance and expose a mechanical valve to thrombosis.
3. Recheck INR at about 24 hours, repeat the dose if still high, and check haemoglobin and urine.
4. Analgesia with paracetamol, no NSAIDs, no intramuscular injections.

Why not fresh frozen plasma FFP is indicated for life-threatening bleeding, or before emergency surgery in an anticoagulated patient. Here it would be given for a number rather than a patient. Its effect is brief (factor VII half-life is only four to six hours), it needs 10-15 mL/kg, and it carries risks of transfusion-associated circulatory overload, transfusion-related acute lung injury and infection. In an anaemic man who may be tipping into heart failure from the bleed, that volume is a real hazard. Prothrombin complex concentrate would be the choice for major bleeding, but it is not warranted or usually available here.

Restarting anticoagulation A mechanical mitral valve is a high thrombotic risk setting. Restart warfarin as soon as the bleeding has stopped and INR is below 3.0, usually within 24-48 hours. If interruption beyond 48-72 hours is unavoidable, bridge with unfractionated or low molecular weight heparin. Arrange dental review, record this as an adverse drug event, and counsel the patient never to accept a new drug without asking about warfarin.

Choosing a non-interacting antibiotic For an odontogenic infection the first-line choice is amoxicillin 500 mg every 8 hours, or amoxicillin-clavulanate if there is spreading cellulitis; clindamycin 300 mg every 6 hours is an alternative in penicillin allergy. All of these have no clinically important effect on warfarin clearance.

Drugs to avoid in this patient:

• Co-trimoxazole (CYP2C9 inhibition) - the culprit here.
• Metronidazole - a very common dental prescription in Nigeria and also a CYP2C9 inhibitor; a classic trap.
• Macrolides such as erythromycin and clarithromycin (CYP3A4 inhibition).
• Fluconazole and, to a lesser degree, ciprofloxacin.
• NSAIDs for pain, because of both gastric erosion and platelet inhibition.

If extraction is needed within 48 hours Do not stop warfarin for a simple extraction. Check the INR on the morning of the procedure and proceed if it is 4.0 or below, which it should be once the current episode is corrected. Use an atraumatic technique, place a suture if needed, apply gauze pressure for 20 minutes and prescribe 4.8% tranexamic acid mouthwash, 10 mL four times daily for two to five days, without swallowing it. Local anaesthetic with adrenaline is acceptable and helpful.

Advise no rinsing, spitting or hot drinks for 24 hours, a soft diet, and to return if bleeding restarts. Because he has a prosthetic valve, give endocarditis prophylaxis - amoxicillin 2 g orally 30-60 minutes before the procedure fits both the valve and the warfarin. If the INR were above 4.0 or the surgery complex, defer, correct the INR and consider hospital admission with heparin bridging.