iy % Coagulopathy Associated j With Vitamin E Ingestion James J. Corrigan, Jr, MD, Frank |. Marcus, Although hypervitaminosis E caus MO @ prolonged prothrombin time and @ hemorrhagic state in animals, excessive vitamin E has not previously been found to cause bleeding in normal humans. We have seen a prolonged pro. thrombin time and ecchymoses develop In a patient who was taking warfarin sodium and clofibrate concomitant with self-administration of vitamin E. The. prothrombin time returned to base line after vitamin E ingestion was stopped while warfarin and clofibrate treatment was continued. Coagulation studies: demonstrated enhanced reduction of the levels of vitamin K-dependent co- agulation factors during the period of vitamin E ingestion, which returned to base-line lev after the patient stopped taking the vitamin, Plasma warfarin levels did not change and platelet function remained normal. The dat ‘gest that patients with vitamin K deficiency may risk hemorrhage if they lake vitamin E. (JAMA 230:1300-1301, 1974) VITAMIN E (tocopherol), a fat-sol- uble vitamin, is very popular in the current treatment that consists of high doses of vitamins given for dis- orders ranging from cardiovascular disease to muscular dystrophy.’ The vitamin can be obtained without pre- scription and it is presumed to be nontoxic to humang?)Serious clinical effects of hypervitaminosis E have not been reported. However our data, clearly show that the addition of mod- erate amounts of vitamin E to the therapeutic regimen of a patient tak- ing warfarin sodium was associated with depressed levels of vitamin K- dependent coagulation factors and clinical evidence of bleeding. Report of a Case A S5-year-old man with arteriosclerotie heart disease and type IV hyperlipo- proteinemia had an inferior wall myocar dial infaretion in May 1973, This was eom- plicated by pulmonary infarction, for Which he was treated ‘with heparin and then warfarin. He was admitted to the University of Arizona Medical Center in and the Cosgulation Research arin Ctra, de Secon faclozy. Deparimert ot Medien (Sr Ma 0), Unversity of zona Mecca! Canter, T- Reorint requests to Deparment of Pediatris, srzona Mocseal Center, Tyoson, AZ 5724 (Or, Conia 1200 JAMA, Dec 2, 1974 # Vol 230, No July 1978 for evaluation of “skipped beats.” Laboratory findings showed nor- mat blood cell counts, normal levels of serum enzymes (creatine phosphokinase, lactic dehydrogenase, serum glutamic oxa loacetic transeminase, and serum glutamic pyruvic transaminase), Blood urea nitro- ‘gen, and bilirubin, ss well as normal uri- nalysis and chest roentgenogram. He was ‘taking warfarin at the time, and the pro- thrombin time was 16.6 seconds (control, 122, Level of serum triglycerides was 801 ‘mg/00 mal (normal, 10 t9 190) and chales- terol, 824 mg/100 ml (normal, 150 to 250). Blectrocardiogram showed Q waves in Teads II, I, and aV,, nonspecific ST-T ‘wave changes, fist degree atrioventricular block, and frequent premature ventricular contractions. The following dosages were prescribed at discharge: warfarin sodium, 5 mg each day; digoxin, 0.25 mg each day iphenglhydantoin, 100 mg four times a day, furosemide, 20 mg three times a day; potassium chloride elixi, 15 ml twice a day; and clofibrate, 500 mg four times a day. Quinidine gluconate was substituted for diphenylhydantoin in August 1978 because of persistent premature ventricular con tractions. In September, the quinidine treatment was discontinued because of diarrhea, and procainamide hydrechloride was prescribed. At this time, the pro- thrombin time was 31.4 sosonds, Warfarin sodium therapy was diseontinued for three days and then given again at a dosage of 5 img each day. ‘Ten days later, the pro- thrombin time was 189 seconds When seen in November 1975, the pa- tient had eechymoses on his arm, abdomen and pubie area. Other eomplaints were re urine and a two-day history of constipa tion. The presence of constipation sug ested the possibility of intra-abdominal Breeding. The prothrombin time was 356 seconds (control, 11.7 seconds) At this time he admitted he had been taking a vitamin E preparation, up to 1,200 international units (UU)/day, for the previous two months. The warfarin and vitamin F trea’, ments were discontinued, and one day later the prothrombin time was 249 sec. fonds and the ecchymoses began to clear ‘Warfarin sodium therapy, but not vitamin Btreatment, was reinsttited, a mg/day dosage alternating with 25 mg/day. ‘The patient, however, was convinced that the| vitamin E was necessary for continued well-being. The following studies were per formed with his consent and full coopera. tion. After his clinical and hematological status had been stable for two months, the Patient was challenged with 800 [Uday of the same vitamin preparation (an over- ‘thecounter brand that contained 99% a-to- copherol). During the test period he took the following medications: digoxin (0.25, mg/day), warfarin sodium (5 mg/day al- ternating with 25 mg/day), elofibrate (500 img four times a day), and procainamide (600 mg four times a day). During the two months before he began taking vitamin E his prothrombin time had ranged between 21 and 28 seconds. The coagulation studies were performed by methods previously de- seribed"* and were performed weekly on Monday mornings before, during, and af- ter the challenge. Plasma for warfarin Tevel determinations was also obtained, During the teat period, the patient did not alter hs diet or take any other prescription ‘or nonprescription drugs including aspirin During the seven-week teat period the results of tests for platelet function re- mained within the normal ranges. These tus included platelet eount, bleeding time (lvy), platelet adhesion to glass. beads, platelet aggregation (with adenosine di phosphate, epinephrine, and collagen), and clot retraction. In addition, plasma coag- ulation factor’ V activity. and fibrinogen concentration remained normal. The Table and Figure show that the prothrombin time was affected by the fourth week (23th day) and progressively increased over the next toro weeks. Plasma warfarin levels did not change. Daring the test period, levels ofthe vita- min K-dependent: procoagulants (factors UM, VIF, TX, and X) declined, assuming their lowest point by the 42nd day. On the 42nd day of vitamin E ingestion, multiple ceechymases appeared on both legs, over the right ankle, on the left arm, and Coagulopathy—Corrigan & Marcuseel Une “a Prothrombin time, 06207 te Prothrombin Time 1+ Vitamin €, 600 1wétay oy a ho Days Taking Vitamin € es 2 8 Days Wot king Vitamin € 3 v2 Plasma Wavtari, ui! “indicates percent of normal human standard. em hematoma appeared in the left retibial area. No mucous membrane leeding was noted. At this time, vitamin E treatment was topped but the warfarin therapy was com inued, and seven days later the prothrom: in time and levels of the coagulation ictors returned (o the same levels as de srmined before the initiation of vitamin B eatment. Concomitantly, al clinieal evi. sce of bleeding disappeared. Comment ‘These data provide evidence that addition of vitamin E to warfarin id clofibrate therapy resulted in a morrhagie state that was due to a duction in the vitamin K-dependent agulation factors If, VII, IX, and X. @ coagulopathy was related to the amin E ingestion since the pro- vombin time and levels of plasma ‘gulation factors did not change ‘ing the two months before the ‘amin had been added to treatment, ere affected after its adminis- tion was introduced. Also, the| sorrhagic state and coagulopathy| ppeared promptly after vitamin astion was discontinued. High| A, Dec 2, 1974 # Vol 230, Nos doses of vitamin E (ie, 2 to 4 gm) are reported not to affect the eoagulation mechanism or cause bleeding in nore mal humans: However, in animal hypervitaminosis E causes a. pro. longed prothrombin time and hemor. hagie state that ean be corested with vitamin K administration?“ [the preciwe mechanism of depresady of the vitamin K-dependent eongulation fector level by vitamin B fas not been determined. This patient was taking warfarin and clofbrate before, during, and af ter vitamin E sdministration. Tis well known that warfarin depresses levels of the vitamin K-dependent co- agulation factors and that lofitrate Potentiates the warfarin effect. Since Clofibrate-treated animals have low and not elevated vitamin Elevels, ite probable thatthe ‘effect of lof. brates related tosynergiom with the amin.” Another posible mecha. im is of drug interaction between warfarin and vitamin E, Ondation of warfarin by the liver iy part of the process by which warfarin is metabo. lized Vitamin Bis an antionidant and may, therefore, retard the deg- radation of warfarin. Evidence to support this thesis was lacking, since plasina warfarin levels did not change substantially during the test period in this patient.(The data suggest, however, that the most likely mecha. nism is the direct interference of vitamin E with vitamin K because there is further depression of the vitamin K-dependent coagulation factor levels in vitamin K-deficient. animals treated with vitamin E2" ‘The recommended daily allowance of vitamin E is 30 TU for adult men and 25 IU for adult women.” Our pax tient was given 800 IU of the vitamin day, or more than 26 times the sug- gested daily requirement. However, the dose is moderate when compared to that recommended and tested" for its beneficial effect on the eardio- vascular system, Present experience suggests that patients with Vitamin K deficiency may risk hemorrhage if they take vitamin BE, + David 5. 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