We investigated various pharmacokinetic and pharmacodynamic parameters in a 63-year-old man, resistant to warfarin, fluindione, acenocoumarol and phenprocoumon. Daily doses of up to 30 mg of the long-acting phenprocoumon yielded a drug concentration of 85 mg/l (usual range 1-5 mg/l) but the international normalized ratio remained around 1. The plasma half-life of phenprocoumon was approximately 350 h (normal 120-150 h). Thus, the resistance was not due to malabsorption or to an accelerated metabolism of the drug. The level of vitamin K1 (1,202 ng/l) was insufficient to induce resistance. Decarboxyprothrombin concentrations were low, demonstrating that the gamma-carboxylation of the precursors of the vitamin K-dependent coagulation factors was not effectively reduced. The concentration of vitamin K epoxide, normally increased under oral anticoagulation, correlated to the vitamin K concentration (r2 = 0.77) but the quotient epoxide/vitamin K remained 4-fold lower than that of 22 warfarin-sensitive patients, suggesting an absence of blockade of the vitamin K reductase by phenprocoumon. This resistance to all the molecular forms of the vitamin K antagonists is most likely due to a reduced affinity of the drugs to a mutant vitamin K reductase.

Drug Resistance↗

PubMedDate not supplied

Complications following total knee replacement.

Forty-two months follow-up examinations on 30 total knee arthroplasties revealed the following significant complications: phlebothrombosis, 13 knees (46%); pulmonary embolism 3 patients (11%); asymptomatic loosening, 8 knees (11.4%); symptomatic loosening, 3 knees (4.8%); superficial infections, 4 knees (5.4%); deep infections, 4 knees (5.4%); peroneal palsy, 3 patients (4.3%). Early detection of thrombophlebitis by 125I fibrinogen scan and possible aspirin prophylaxis were evaluated. In view of the limited number of encouraging results, e.g. excellent 58.6 per cent; good 28.5 per cent; fair 5.4 per cent and poor 7.1 per cent, caution is advocated until extensive time elapses for more clinical experience with total knee arthroplasty.

Adult↗