Haemorrhage/bleeding warfarin

Drug interaction Warfarin and thyroxine are frequently taken togetirer especially in elderly patients. This combination is thought to be a source of adverse bleeding due to the thyroxine-dependent potentiation of warfarin effects. The results of a 16-year-population-based nested case-control study in which 10,532 patients hospitalised for haemorrhage were matched with 40,595 controls could not substantiate this interaction. There was no increased risk of haemorrhage in warfarin-treated patients receiving levothyroxine up to 30 days (odds ratio (OR) of 1.11,95% Cl of 0.67-1.86), 60 days (OR of 0.76) or 90 days (OR of 0.67) prior to hospitalisation [13 ]. 

Animals fed spoiled sweet clover were prone to fatal haemorrhages. The canse was traced to the presence of dicoumarol. This compound interferes with the effects of vitamin K in blood coagulation, the blood loses its ability to clot, and minor injnries can lead to severe internal bleeding. Synthetic dicoumarol has been nsed as an oral blood anticoagnlant in the treatment of thrombosis, where the risk of blood clots becomes life threatening. It has since been snperseded by warfarin, a synthetic development based on the natnral prodnct. 

The only major side-effect of these oral anticoagulants is prolonged bleeding, thus the dosage levels are chosen with care. Dicoumarol was first isolated from spoiled sweet clover hay, as the agent which promoted haemorrhage disease in cattle. Both dicoumarol and warfarin have also been utilized (at high doses) as rat poisons. 

May cause easy bruising and excessive bleeding from minor injuries. Reports of haemorrhage with concomitant use of warfarin and dan shen. INR may not always be altered. Case report with ginseng of normal coagulation studies during postoperative bleeding... 

Warfarin + mefenamic acid Enhanced anticoagulant blood levels with risk of haemorrhage and enhanced risk of Gl bleeding Displacement from protein Concurrent administration is best avoided. If necessary, coagulation limes should be monitored... 

At least 7 reports have described increased prothrombin times or INRs in patients stabilised on warfarin who took flueonazole in doses of 50 to 400 mg daily. " Several patients had haemorrhagic effects (gastrointestinal bleeding, melaena, ocular haemorrhage, spinal epidural haemato-... 

A number of studies and case reports have confirmed this interaction with warfarin. In the studies, plasma warfarin levels were reported to rise by 25% and 80%, and prothrombin times were increased by 18% and 20% by cimetidine 1.2 g daily. In the case reports, severe bleeding (haematuria, internal haemorrhages) and very prolonged prothrombin times have been seen in few patients given cimetidine 900 mg or 1.2 g daily 4,e-s jjj Qjjg 7 out of 14 patients stabilised on warfarin had a... 

Evidence from pharmacological studies in patients and healthy subjects su ests that Ginkgo biloba extracts do not interact with warfarin. However, an isolated report describes intracerebral haemorrhage associated with the use of Ginkgo biloba and warfarin, and there are a few reports of bleeding associated with the use of ginkgo alone. 

Etoricoxib, lumiracoxib and rofecoxib caused a slight 8% to 15% increase in the INR in response to warfarin, whereas celecoxib and parecoxib had no effect. However, raised INRs accompanied by bleeding, particularly in the elderly, have been attributed to the use of waHarin and celecoxib or rofecoxib in other reports. In addition, in a case-control study in patients taking warfarin, the use of celecoxib or rofecoxib was associated with an increased risk of hospitalisation for upper gastrointestinal haemorrhage, which was of a similar magnitude to that seen with non-selective NSAIDs. 

Limited evidence su ests that the combined use of intravenous high-dose epoprostenol and warfarin may increase the risk of pulmonary haemorrhage. Continuous subcutaneous treprostinil did not alter the pharmacokinetics or the INR in response to singledose warfarin, and also did not appear to increase the risk of bleeding when used with warfarin in clinical studies. Because these prostaglandins inhibit platelet a regation, some caution is appropriate on combined use with anticoagulants. 

An isolated case describes a patient who had an increase in her INR the day after starting valproic acid, but was eventually restabilised on the original dose of warfarin while still taking the valproic acid. Valproic acid did not alter the anticoagulant effects of phenprocoumon in one patient. Valproate alone can cause altered bleeding time, bruising, haematoma, epistaxis and haemorrhage. 

In 1952, an army recruit attempted suicide by taking rat poison containing warfarin. On admission to hospital he had numerous subcutaneous haemorrhages and was suffering from nose-bleeds. His prothrombin time was 54 seconds, compared with a normal value of 14 seconds. (The prothrombin time is the time taken for the formation of a fibrin clot in titrated plasma after the addition of calcium ions and thromboplastin to activate... 

The symptom of vitamin K deficiency is increased risk of haemorrhage, ease of bruising, nose bleeding and blood in the urine. In infants, vitamin K deficiency may result in intracranial bleeding. Vitamin K deficiency is rare in adults although vitamin K status is assessed in the newborn and in the USA a routine injection of vitamin K is recommended for newborn babies, particularly premature babies where the vitamin K cycle may not be fidly established. Human breast milk is relatively low in vitamin K. There has been some controversy over whether or not childhood leukaemia can be linked to injection of newborns with vitamin K, but a large retrospective study fotmd no link. Certain dmgs such as warfarin, sulphona-mides and cephalosporins can affect vitamin K function. 

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