Warfarin necrosis
A rare but serious complication resulting from treatment with warfarin is warfarin necrosis, which occurs more frequently shortly after commencing treatment in patients with a deficiency of protein C, an innate anticoagulant that, like the procoagulant factors whose synthesis warfarin inhibits, requires vitamin K-dependent carboxylation for its activity. Since warfarin initially decreases protein C levels faster than the coagulation factors, it can paradoxically increase the bloods tendency to coagulate when treatment is first begun (many patients when starting on warfarin are given heparin in parallel to combat this), leading to massive thrombosis with skin necrosis and gangrene of limbs. Its natural counterpart, purpura fulminans, occurs in children who are homozygous for certain protein C mutations. Osteoporosis
After initial reports that warfarin could reduce bone mineral density, several studies demonstrated a link between warfarin use and osteoporosis-related fracture. A 1999 study in 572 women taking warfarin for deep venous thrombosis, risk of vertebral fracture and rib fracture was increased; other fracture types did not occur more commonly. A 2002 study looking at a randomly selected selection of 1,523 patients with osteoporotic fracture found no increased exposure to anticoagulants compared to controls, and neither did stratification of the duration of anticoagulation reveal a trend towards fracture.A 2006 retrospective study of 14,564 Medicare recipients showed that warfarin use for more than one year was linked with a 60% increased risk of osteoporosis-related fracture in men, but no association in women was seen.
The Cleveland Clinic suggests that when taking warfarin one should not drink more than "one beer, 6 oz of wine, or one shot of alcohol per day".Warfarin also interacts with many herbs and spices, some used in food (such as ginger and garlic) and others used purely for medicinal purposes (such as ginseng and Ginkgo biloba). All may increase bleeding and bruising in people taking warfarin; similar effects have been reported with borage (starflower) oil. St. Johns wort, sometimes recommended to help with mild to moderate depression, reduces the effectiveness of a given dose of warfarin; it induces the enzymes that break down warfarin in the body, causing a reduced anticoagulant effect.Between 2003 and 2004, the UK Committee on Safety of Medicines received several reports of increased INR and risk of haemorrhage in people taking warfarin and cranberry juice. Data establishing a causal relationship are still lacking, and a 2006 review found no cases of this interaction reported to the USFDA; nevertheless, several authors have recommended that both doctors and patients be made aware of its possibility. The mechanism behind the interaction is still unclear. Chemistry
X-ray crystallographic studies of warfarin show that it exists in tautomeric form, as the cyclic hemiketal, which is formed from the 4-hydroxycoumarin and the ketone in the 3-position substituent. However, the existence of many 4-hydroxycoumadin anticoagulants (for example phenprocoumon) that possess no ketone group in the 3-substituent to form such a structure, suggests that the hemiketal must tautomerise to the 4-hydroxy form in order for warfarin to be active.