Prothrombin time control

The international normalized ratio (INR) is a method to standardize repotting of the prothrombin time, using the formula, INR = (PTpatie t/PTcontroi)ISI, where PT indicates the prothrombin times (for the patient and the laboratory control), and ISI indicates the international sensitivity index, a value that varies, depending upon the thromboplastin reagent and laboratory instrument used to initiate and detect clot formation, respectively. 

Coumarins are competitive inhibitors of vitamin K, which is required for the formation in the liver of the amino acid, gamma-carboxyglutamic acid. This is necessary for the synthesis of prothrombin and factors VII, IX and X (Figure 17.1). After starting treatment the anticoagulant effect is delayed until the concentration of normal coagulation factors falls (36-72 h). The effects can be reversed by vitamin K (slow maximum effect only after 3-6 h) or by whole blood or plasma (fast). Gut bacteria synthesise vitamin K and thus are an important source of this vitamin. Consequently, antibiotics can cause excessive prolongation of the prothrombin time in patients otherwise adequately controlled on warfarin. 

The prothrombin time (PT) is used to monitor anticoagulation. The patient s PT is determined along with that for a control sample of plasma, and the two values are often reported as a ratio. Because this ratio can vary widely between laboratories, the INR system of reporting has been adopted. The INR is the ratio of the patient PT to a control PT obtained by a standard method using a World Health Organisation primary standard (human) thromboplastin. PT measurements are converted to INR measurements by the following equation ... 

Milk thistle has been used to treat acute and chronic viral hepatitis, alcoholic liver disease, and toxin-induced liver injury in human patients. Milk thistle has most often been studied in the treatment of alcoholic hepatitis and cirrhosis. In both of these disorders, outcomes have been mixed and reports include significant reductions in markers of liver dysfunction and in mortality, as well as no effect. In acute viral hepatitis, studies have generally involved small sample sizes and have shown mixed outcomes of improved liver function (eg, aminotransferase values, bilirubin, prothrombin time) or no effect. Studies in chronic viral hepatitis and toxin-induced injury have also been of small size but have reported mostly favorable results. Parenteral silybin is marketed and used in Europe as an antidote in Amanitaphalloides mushroom poisoning, based on favorable outcomes reported in case-control studies. 

The prothrombin time (FT), which is usually expressed as the International Normalised Ratio (INR) for control of oral anticoagulant therapy, primarily evaluates the extrinsic system. 

Potentiation of the effects of vitamin K antagonists by high-dose intravenous methylprednisolone has been prospectively studied in 10 consecutive patients and 5 controls after the observation of a sharp increase in the International Normalized Ratio (INR) in a patient taking oral anticoagulation after concomitant administration of methylprednisolone (1 g/day for 3 days) (262). The mean INR was 2.8 (range 2.0-3.8) at baseline and increased to 8.0 (5.3-20). The maximum increase in INR occurred after a mean of 93 (29-156) hours. The coumarins taken by these patients were fluindione in eight and acenocoumarol in two. The prothrombin time in the controls... 

In an early, double-blind, placebo-controlled study of the interaction between coumarin anticoagulants and paracetamol, there was a statistically significant lengthening of the prothrombin time (124). The effect, although statistically significant, was very small and was considered to be clinically unimportant. 

While terbinafine had no effect on warfarin in healthy volunteers, it can prolong the prothrombin time in some individuals (74-77), prompting intensification of laboratory control during terbinafine therapy. 

Dicoumarol, warfarin + laxatives Chronic laxative administration may cause loss of anticoagulant control Two possible effects lubricant oil action may cause decreased absorption of anticoagulant decreased absorption of vitamin K, particularly with oils and emulsions Periodic long-term monitoring of prothrombin times in all suspect patients... 

A significant number of patients with HCM develop atrial fibrillation. Amiodarone is one of the most effective agents available to maintain normal sinus rhythm in these patients. For patients in chronic atrial fibrillation requiring rate control, a -blocker or verapamil may be used." Anticoagulation should be considered because these patients are at a risk for systemic embolization and stroke. If amiodarone is added to a patient already receiving warfarin, the prothrombin time or international normalized ratio (INR) wfll be increased and should be monitored closely. 

Prothrombin Time (WB) Less than 2 sec deviation from control ... 

In one study, 15 alcoholics who had been drinking heavily (250 g ethanol or more daily) for at least 3 months and 11 control subjects (minimal social drinkers or non-drinkers) were given a single 40-mg dose of warfarin. The half-life of warfarin was lower in the alcoholics (26.5 versus 41.1 hours), but a comparison of the prothrombin times with those of healthy subjects found no differences. ... 

In a placebo-controlled, randomised, crossover study, 10 healthy subjeets were given losaitan 100 mg daily for 13 days with a single 30-mg dose of warfarin on day 7. The pharmacokinetics of warfarin (both R- and S-enantiomers) and its anticoagulant effects were not altered. Losaitan, given alone for a week, also had no effect on prothrombin times. ... 

In a controlled study in 7 patients stabilised on warfarin and without infections, dicloxacillin 500 mg four times daily for 7 days reduced the mean prothrombin time by 1.9 seconds. One patient had a 5.6 second reduction. This study was conducted because the authors had noted a case of a patient receiving warfarin who had a decrease in prothrombin time when dicloxacillin was started. Another patient stabilised on warfarin had a 17% fall in prothrombin times within 4 to 5 days of starting dicloxacillin 500 mg four times daily, with a documented 20 to 25% reduction in both S- and R-warfarin levels. In a retrospective review, 7 other patients similarly treated were also identified as having a 17% reduction in pro-... 

A patient stabilised on warfarin (prothrombin ratio 2), developed a purpuric rash and bruising within 6 days of starting nalidixic acid 500 mg four times daily. Her prothrombin ratio had risen to 3.46. Another patient, previously well controlled on warfarin, developed a prothrombin time of 60 seconds 10 days after starting nalidixic acid 1 g three times daily.The INR of an 84-year-old woman taking warfarin rose from 1.9 to 9.6 when nalidixic acid was added. Similarly, a patient taking acenocoumarol developed hypoprothrombinaemia after receiving nalidixic acid 1 g daily. ... 

Isolated cases suggest that doxycycline and tetracycline can increase the effects of coumarins. Similarly, some small studies (none controlled) suggest that chlortetracycline (alone or with oxytetracycline), doxycycline, or the tetracyclines as a class may increase the risks of over-anticoagulation, but there appear to be no studies of the effect of tetracyclines on the pharmacokinetics of coumarins. However, the related antibacterial, tigecycline, increased the AUC of warfarin, and has been shown to increase the prothrombin time when given alone. 

In an early clinical study, 25 patients with colon cancer were given bolus fluorouracil 15 to 20 mg/kg weekly plus warfarin daily, titrated to maintain the prothrombin time in the 20 to 30% range, and modified weekly as necessary. Three patients developed blood loss from the gut, which was controlled by giving a transfusion and stopping the warfarin. This study did not report the required dose of warfarin, or how often it needed adjusting in these patients. ... 

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