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The Dangers of Dicumarol Therapy
THE DANGERS OF DICUMAROL THERAPY ELBERT T. PHELPS, M.D.* DEATH and disability from Dicumarol therapy are no longer a rarity. DufF recently reviewed twenty-two published cases of death in patients receiving Dicumarol and added one previously unpublished case. Lilly and Lee2 added five more fatal cases and also report on four cases of very serious bleeding during Dicumarol anticoagulant therapy and one case of recurrent thromboembolic disease after cessation of adequate therapy. There is little question of the therapeutic and prophylactic efficacy of Dicumarol in thromboembolic disease 3 and myocardial infarction. 4 But some of the inherent dangers and contraindications to Dicumarol medication may justifiably be reemphasized at this time and some suggestions for the prevention of dangerous hypoprothrombinemia and bleeding are appropriate, for the lack of agreement among acknowledged authorities in this field is transmitted to practitioners as misinterpretation and dissatisfaction with laboratory data which may appear too inaccurate to guide Dicumarol dosage. CONTRAINDICATIONS TO THE USE OF DICUMAROL
Several contraindications to the use of Dicumarol have gradually accumulated. Death or severe disability has followed use of the dmg in some of the conditions listed in Table 1. TABLE 1 CONTRAINDICATIONS TO THE USE OF DICUMAROL THERAPY
Absolute Subacute bacterial endocarditis Purpura and blood dyscrasias Brain or cord surgery Advanced liver disease Jaundice and impaired absorption of vitamin K Expectation of immediate surgery Advanced kidney disease Active gastrointestinal bleeding Large ulcerating lesions Exposure to severe trauma Lat~ in pregnancy Regional aneBthesias and blocks Inadequate laboratory facilities
Relative Lack of blood for transfusion Lack of Vitamin Kt or Kl oxide History of bleeding ulcer Injection therapy (deep) Emaciation and malnutrition Hypertension and arteriosclerosis Generalized capillary disease
From the Department of Medicine, Geotgetown University Hospital and Georgetown University School of Medicine, Washington, D. C. * Instructor in Medicine, Georgetown University School of Medicine; Visiting Physician, Georgetown University Hospital. 1791
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Absolute Contraindications. The use of Dicumarol without clinical or laboratory check of the patient cannot be too strongly condemned, and if the patient does not know that he is receiving a dangerous drug which may cause bleeding, the situation is even \vorse (see Cases I and II). Because of the nature of subacute bacterial endocarditis and the likelihood of cerebral emboli, bleeding within the brain may follow deficiency in coagulation mechanism. Dicumarol therapy is an added hazard. Seven deaths in patients with subacute bacterial endocarditis who were treated with Dicumarol have been collected. l Parenthetically, anticoagulants have not been found to benefit the course of subacute bacterial endocarditis treated with antibiotics or sulfonamides. One could expect the bleeding tendency of purpura to be dangerously potentiated by anticoagulant therapy; and many of the blood dyscrasias have overt or latent bleeding tendencies which one would expect Dicumarol to increase (see Case V). With a past history of purpura one would profit by performing a bleeding work-up, consisting of a tourniquet test, prothrombin, bleeding, clotting and clot retraction times and a platelet count before beginning therapy. At toxic levels Dicumarol causes abnormalities in the bleeding time and coagulation time as well as in prothrombin time (see Case V). Following brain or spinal cord surgery (also ophthalmologic and some kinds of plastic surgery) small collections of blood may have disastrous effect, and Dicumarol is inadvisable, though there is probably no greater tendency to bleed than in other random cases. Lumbar puncture and cisternal puncture are dangerous because they may result in bleeding into confined spaces, with damage to the nervous system. Severe bleeding in a large series of postoperative cases treated with Dicumarol occurred in 1.9 per cent and mild bleeding (epistaxis, hematuria, petechiae and ecchymoses) in 3.1 per cent of 1686 patients 3. Advanced liver disease frequently results in a fall in prothrombin production. Though the exact site of action of Dicumarol is not absolutely known to be upon the metabolism of vitamin K and the formation of prothrombin by the liver, Dicumarol in the usual therapeutic doses may cause a severe, prolonged drop in the prothrombin contentS but smaller doses may be used with great care. 7 Patients with cirrhosis (with or without esophageal varices or hemorrhoids), severe acute hepatitis, chronic hepatitis, obstructive jaundice, steatorrhea or sprue and severe malnutrition are poor subjects for Dicumarol therapy. Intestinal coliform bacteria which form vitamin K are inhibited in the intestinal tract by oral streptomycin, sulfonamides and probably aureomycin and chloramphenicol and terramycin. This may be an overlooked cause of the unexplained changes in sensitivity of patients to Dicumarol when taking sulfonamides or antibiotics over long periods of time. The site of degradation and excretion of Dicumarol is not known but
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advanced kidney damage may cause excess response to Dicumarol and is a contraindication to its use. 3 Immediate surgery is contraindicated after fall in the prothrombin content during Dicumarol therapy; but transfusion and the intravenous injection of suspensions of 1000 mg. of the vitamin KI aid in returning the prothrombin content to safe levels in six to twenty-four hours if dangerous depression is present and surgery needed. If immediate surgery is in prospect, the danger of postoperative hemorrhage and wound dehiscence is an obstacle to the use of Dicumarol. One of our patients died following thoracentesis, certainly a very minor procedure, done while the prothrombin level was diminished by Dicumarol (see Case IV). Gastrointestinal bleeding, if active, is an absolute contraindication to the use of Dicumarol since it has been found that even after vigorous therapy the patient may continue to bleed severely. Davidson's fatal case demonstrated the marked prolongation of coagulation time seen with severe hypoprothrombinemia in Dicumarol poisoning, 8 but in neither his nor AlIen's case3 was an active peptic ulcer present prior to institution of anticoagulant therapy, though there had been previous peptic ulcers in both. Ulcerating lesions of all kinds, unless small, must be serious deterrents to the use of anticoagulants; malignancies, deep burns, active and probably inactive ulcerative colitis, and even large chronic phlebitic ulcers must be evaluated carefully before instituting therapy. As an example a patient of Allen3 with metastatic carcinoma of the duodenum, despite adequate prothrombin control, died of gastrointestinal hemorrhage after operation. When there is likelihood of exposure to severe trauma, ambulatory therapy with Dicumarol should not be used (see Case II). Children, except those in well controlled pediatric wards, laborers, farmers and athletes are particularly subject to severe trauma, predisposing to severe hemorrhage from lacerations, ecchymoses or hematomas which may cause massive tissue breakdown, deformity or death. At this time mention should be made of the patients with venous thrombosis or arterial occlusion of the lower extremity, now so frequently treated with Dicumarol, who receive paravertebral lumbar sympathetic regional injections with alcohol or local anesthetics. Lilly 2 collected four such fatal c.J,ses in which very severe contiguous and distant hemorrhage occurred. Similarly, regional injections for tic doloreaux, brachial plexus block, sacral block, perineal block, intercostal block and others should be unuertaken with extreme caution if at all and spinal anesthesia is definitely contraindicated during Dicumarol therapy. Lilly also reported a patient in whom the combination of a skeletal traction with a Steinman pin and Dicumarol therapy resulted in dangerous and severe hemorrhage into the extremity. Another patient had permanent deformity and long disability following the injection of penicillin in the gluteal region during
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therapy. If injections must be given during Dicumarol therapy, smallbore needles and easily absorbable products should be used. Newborn, especially premature infants, have a low prothrombin content even though their mothers have normal or even elevated levels. 9 The use of Dicumarol in the mother before delivery may cause serious bleeding in the child and increase the dangers of cerebral and other hemorrhages. 1o Both Quickll and Kraus10 demonstrated that induction of experimental hemorrhagic sweet clover disease in pregnant animals could cause death of offspring in utero or soon after birth. Because the newborn lack intestinal bacteria to form vitamin K they are unusually sensitive to Dicumarol in the first few days of life. After approximately ten years of clinical experience with Dicumarol, the chief contraindication to its use is still the lack of adequate laboratory control, or the lack of proper clinical use of the laboratory results. "Adequate laboratory control" infers the daily checking of plasma prothrombin prior to ordering that day's dose of Dicumarol. It also means a prothrombin determination done by a well trained technician, able to very closely reproduce her results on successive determinations with the same plasma and thromboplastin preparation, under the direction of a clinical pathologist. Proper clinical use of prothrombin determinations is most severely hindered by widespread misinformation among physicians concerning multiplicity of prothrombin tests and their many variations. In addition, different experts set up very different standards for interpretation of their own and others' prothrombin tests of normal, dilute and Dicumarol plasmas. For example, the original Quick test is so designed that the normal prothrombin time is 11 to 12t seconds. The unknown prothrombin times are expressed in "prothrombin activity" as per cent of normal derived from a fixed hyperbolic curve obtained through determinations of the prothrombin time of certain dilutions of normal plasma.H But the experts differ widely in their thromboplastin source and extraction, and use different diluents for the plasma. These variations cause changes in the normal prothrombin dilution curve. The normal prothrombin time for undiluted plasma varies from 11 to 19 seconds with tests in common clinical use. However, a plasma with a prothrombin time of 19 seconds by the original Quick method would be reported as havin..; 30 per cent activity. The practical result is that a physician getting reports from several neighboring hospitals or laboratories may have reports on prothrombin determinations done by a two-stage method with and without the AC-globin refinement,l2b upon whole fresh venous blood ("bedside method"),llc or by the very numerous variations of Quick's method. Hence the clinician may receive data expressed in the wrong unitage for the test used (see our Case IV), or may receive the data in the correct unitage but order anticoagulant according to accepted standards for
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another test, which he may have been accustomed to using in a neighboring hospital. The result may be either dangerous hypoprothrombinemia or insufficient depression of the coagulation for prevention of thromboembolic disease. Relative Contraindications. Healed peptic ulcer patients have suffered activation of these ulcers with fatal results as already mentioned,3, 8 the cause of the reactivation being unknown. The danger of deep injection therapy such as in regional anesthesia and alcohol nerve block during Dicumarol therapy have been mentioned, but even smaller and less traumatic injections should be kept at a minimum. Hypertension and arteriosclerosis have been associated with four of the published reports of death from Dicumarol therapy.1, 16 It is proposed16 that hypertension and arteriosclerosis damage the vascular endothelium allowing diapedesis. Link17 feels very strongly that vitamin C is a protective agent during Dicumarol therapy to influence the degree and duration of hypoprothrombinemia and the capillary integrity in the rat, the rabbit and guinea pig. Vitamin P deficiency has been implicated in vascular disease so that both vitamin P and C may also play a part in the tendency of hypertensive and arteriosclerotic patient to hemorrhage. The aged also appear to be more sensitive to Dicumarol but this may be a result of their arteriosclerosis. At present blood or plasma transfusions and vitamin K are the only effective antagonists of severe poisoning with Dicumarol. Citrated banked blood as well as fresh blood and bank plasma are similarly effective but give only mild and transient rise in the prothrombin concentration when the deficiency is severe. Most of the patients who have died of Dicumarol poisoning were treated unsuccessfully with blood and large doses of water-soluble vitamin K preparations. The phytyl side chain found in the oil-soluble vitamins K1 and K1 oxide appears to be necessary for reversal of severe Dicumarol intoxication.7, 13. 14, 15, Deficiency of prothrombin occurring during impaired ingestion or absorption of vitamin K does, however, respond to the water-soluble vitamin K products. Patients probably should not receive Dicumarol unless, in addition to reliable prothrombin determinations, the hospital has vitamin KI (or vitamin KI oxide) and blood for transfusions for emergency treatment when severe bleeding results. ILLUSTRATIVE CASES CASI'; 1. A 54 year old white man entered Georgetown University Hospital in November 1949 because of extremely severe swelling of the side of his face and displacement of his tongue causing respiratory distress. Dicumarol, apparently in 100 mg. daily doses, had been started one month before, because of chest pain and an abnormal electrocardiogram. He rested at home while taking the anticoagulant, vitamins and sedatives. About one week before entry his gums began
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to bleed and he saw his dentist who probed without effect except to increase bleeding, finally necessitating tooth extraction. Almost immediately a large hematoma began to form in the floor of the mouth and in the left cheek, finally displacing the tongue backward and closing the eye. Family and personal history were irrelevant. Physical examination was normal except for the face, mouth and neck. The left eye was completely closed; the left side of the face was very full and reddishblue in color. Ecchymoses were present on buccal, gingival and palatal mucosa. The tongue was displaced to the right and posteriorly and a large soft clot was present in the oropharynx. Marked anemia (hematocrit 22), grossly bloody urine containing 3 plus albumin and tarry, guaiac-positive stool were found. The initial bleeding work-up disclosed no abnormalities other than a prothrombin content of less than 10 per cent. A repeat clotting time by the Lee-White method was sixteen minutes. Therapy consisted of 780 mg. of Synkayvite and 1000 cc. of whole blood. On the fifth day of hospitalization the patient's physician discharged him despite a prothrombin time of 45 seconds (less than 10 per cent:content). On three occasions the oral clot had required manual removal to prevent blockage of the airway.
Comment. A near fatality from Dicumarol therapy occurred because the prothrombin levels were not checked. Dental surgery was done despite a clinical bleeding tendency of very recent duration. Insufficient blood transfusions and no vitamin Kl were given, and finally the patient was discharged while still critically hypoprothrombinemic. CASE H. A 17 year old Negro youth was readmitted to Gallinger Municipal Hospital on January 10, 1949, with the history that he had been discharged two weeks before with the diagnosis of an acute myositis but without specific therapy. The second admission was for right flank pain and grossly bloody urine which followed an athletic injury. History of anticoagulant therapy could not be elicited. Emergency pyelography was suggestive of perirenal hemorrhage on the right side. Urinary bleeding increased during the first few hours of hospitalization and operation followed. A large perirenal hemorrhage was found. Severe oozing into the operative field could not be stopped and borderline shock developed. Prothrombin determinations taken while the patient was in surgery were prolonged to more than 70 seconds. Continuous whole blood transfusions were given along with 72 mg. of Synkayvite every four hours. On the second day 72 mg. of Synkayvite was given to a donor and twelve hours later 500 cc. of blood withdrawn to give to the patient; no apparent improvement resulted. After six days the prothrombin level rose to 30 per cent or more of normal and remained there, and bleeding stopped. On ward rounds on the seventh day a visiting physician, suspicious because of a similar case of his own, elicited the history that the boy had seen a doctor who prescribed pills for "a blood clot in the arm." Confirmation that 300 mg. of Dicumarol had been taken in the four days before admission was obtained. He was discharged on February 4,1949.
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Comment. Since the use of Dicumarol has become so widespread and somewhat indiscriminate, careful questioning regarding Dicumarol therapy is necessary in all unusual bleeding cases. A near fatality and unnecessary surgery occurred because the patient was not told about his therapy. A prothrombin determination and possibly a complete bleeding work-up may be necessary in such cases, and surgical procedures should not be performed without corrective therapy with blood transfusions and vitamin K 1. Ambulatory therapy with Dicumarol should not be used without a preceding period of hospitalization for dosage regulation. Patients should be told of the nature and dangers of their therapy. CASE Ill. A 46 year old white single man entered Georgetown University Hospital on January 27, 1950 because of recurrent substernal pain of eleven days' duration. The electrocardiogram revealed evidence of recent myocardial infarction and Dicumarol was started. The patient's physician made daily prothrombin determinations in his own downtown laboratory and prescribed Dicumarol based on his prothrombin determinations, which indicated that the patient was "resistant" to Dicumarol. On the twenty-eighth hospital day the patient had a severe nosebleed which could not be stanched. This was after a total dose of 4800 mg. of Dicumarol, and with a prothrombin of 21.6 seconds (23 per cent content) (modified Quick method) by the physician's laboratory. The prothrombin by the Georgetown University Hospital Clinical Laboratory was 40.3 seconds (less than 10 per cent content) (modified Quick method). Ten milligrams of Synkayvite and 72 mg. of menadione sodium bisulfite U.S.P. were given. Gradually diminishing bleeding (total loss of 500 cc.) occurred for four days, during part of which time the patient refused to sleep because he feared he would bleed and drown in blood. The prothrombin content remained less than 30 per cent for four days after the first bleeding, and returned to normal on the fifth day
Comment. A dangerously low prothrombin content and hemorrhage resulted after almost one month of Dicumarol dosage which averaged about twice the usual daily dose because of apparent insensitivity. Exchange of views on details of prothrombin determination among the laboratories in a natural geographical area, such as Washington, D.e. and suburbs, might obviate tragic errors. Standardization of technic and a system of mutual checking could be initiated. A necessary factor would be a common source for a preparation of thromboplastin. In contrast to some laboratory procedures where a 10 per cent error is inconsequential, such an' error in prothrombin might cause death from pulmonary emboli by use of too little Dicumarol or death from hemorrhage through use of too much. CASE IV. An elderly white man was admitted to a hospital in late 1949 because of abdominal pain and shortness of breath. The signs of hypertensive
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cardiovascular disease, cardiac decompensation, myocardial infarction and left hydrothorax were found on hospitalization. Several thoracenteses disclosed a yellowish nonbloody fluid prior to Dicumarol therapy. Dicumarol was begun on the ninth hospital day and was continued for fifteen days, the total dose being 1300 mg. The longest prothrombin times recorded were 76.8 seconds on the tenth day of Dicumarol therapy and 96 seconds nineteen days after the onset of therapy. A Dicumarol therapy sheet was used which gave the control prothrombin time, the patient's prothrombin time, the dose of Dicumarol and the graphic per cent of normal prothrombin time. The latter was calculated by dividing the control prothrombin in seconds by the patient's prothrombin in seconds. Because fluid reaccumulated in the left chest thoracenteses were done after Dicumarol was started, bloody fluid being obtained. Twenty-seven days after admission and eighteen days after beginning Dicumarol the patient expired with signs of shock and left hemothorax despite several transfusions and 144 mg. of Hykinone intravenously. Thoracentesis just before death gave "1200 cc. of blood." Postmorten examination was performed.
Comment. The laboratory error in reporting the prothrombin by dividing the normal or control time by the patient's time was out of line with the prothrombin time in seconds and could have been spotted. This is a very common error and may be one reason for serious bleeding in patients with recorded prothrombin levels above 30 per cent.'S In the bedside whole blood method of Smith the patient's prothrombin is, however, calculated just this way, further indicating the need for standardization of procedures and nomenclature. Thoracentesis probably should not have been done during the Dicumarol therapy. A single standard laboratory procedure is a present necessity for safe Dicumarol therapy. CASE V. A 68 year old widow entered Georgetown University Hospital in April 1950 because of painless and later very painful hematuria of one day's duration. Four weeks before admission she had developed a phlebothrombosis of the leg and was placed on Dicumarol in doses of 200 mg. the first, 100 mg. the second, and 50 mg. daily maintenance. Prothrombin time had been within therapeutic range on checking it every two days in a clinical laboratory until the drug was stopped. The drug was stopped seven days prior to admission. Watersoluble vitamin K given at home had no apparent effect. The patient had always bruised easily but had never been troubled by it. Examination showed many petechiae over the legs and an ecchymoses on the left thumb and right arm. Bleeding work-up showed a prothrombin content of less than 10 per cent, platelet count of 68,000, clotting time of twenty minutes and 4 seconds, bleeding time of seven minutes and 55 seconds, positive RumpelLeed test and diminished clot retraction. Marked hematuria and albuminuria were present. Severe bilateral renal colic developed despite intravenous Hykinone 72 mg. every three hours for twenty-four hours, and 1000 cc. of whole blood. After receiving 1000 mg. of vitamin K, suspension intravenously, the prothrombin rose to 66 per cent content and renal colic subsided. However, six days later
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severe right renal colic recurred and the prothrombin determination showed 33 per cent content (modified Quick method). An additional 1000 mg. of vitamin KI intmvenously was given and the prothrombin level rose to 57 per cent content without further relapse. A pyelogram done later was normal. A platelet count of 56,000 was found after the bleeding tendency had stopped.
Comment. Ambulatory use of Dicumarol without previous standardization of dosage in the hospital is dangerous. Sudden changes in sensitivity or response to the drug are recorded in the literatUre. Hematuria and renal colic in patients receiving Dicumarol should be a tip-off to watch closely and check prothrombin levels. The history of easy bruising is not an unusual one but perhaps should have stimulated a test of bleeding tendencies before therapy, though a platelet count of 60,000 is usually not accompanied by purpura or diminished clot retraction. SUMMARY AND CONCLUSIONS
Contraindications to the use of Dicumarol have been presented with some illustrative case reports from several hospitals in a representative community. The dangers of Dicumarol therapy are at least partially the result of the use of a very potent drug whose dosage depends on a test, the prothrombin determination, which is at present insufficiently standardized in the clinical laboratories and insufficiently understood by many physicians. The physician who knows the contraindications to Dicumarol therapy, the specific prothrombin test used on his patients, the correct therapeutic range and controls the drug dosage to attain the proper level will rarely encounter dangerous bleeding. If the prothrombin results are out of line with clinical appearance the clinician should check with the laboratory where he may find errors in technic and terminology. Standardization of thromboplastins, prothrombin determinations and terminology on a local basis may obviate deaths and disability from errors in Dicumarol therapy. REFERENCES 1. Duff, 1. F. and Shull, W. H.: Fatal Hemorrhage in Dicumarol Poisoning. J.A.M.A. 139:762-766, 1949.
2. Lilly, G. D. and Lee, R. M.: Complications of Anticoagulant Therapy. ,Surgery 26:957-967,1949. 3. Allen, E. V.: The Clinical Use of Anticoagulants, Report of Treatment with Dicumarol in 1,686 Postoperative Cases. J.A.M.A. 134:323-329, 1947.
4. Wright, 1. S., Marple, C. D. and Beck, D. F.: Anticoagulant Therapy of Coronary Thrombosis with Myocardial Infarction. J.A.M.A. 138:10741079, 1948 ..
5. Link, K. P.: Dicumarol-and the Estimation of Prothrombin, or "The
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World, The Flesh and/or the Devil." Blood Clotting and Allied Problems, Josiah Macy, Jr. Foundation, New York, Tr. of the First Conference Feb. 16-17, 1948, p. 130. 6. Reisner, E. H., Norman, J., Field, W. W. and Brown, R.: The Effect of Liver Dysfunction on the Response to Dicumarol. J. Clin. Investigation 28:445-447, 1949. 7. Harvey, W. P. and Finch, C. A.: Dicumarol Prophylaxis of Thromboembolic Disease in Congestive Heart Failure. New England J. Med. 242:208-211, 1950. 8. Davidson, C. S., Freed, J. H. and MacDonald, H.: The Effect of Vitamin Kl Oxide Upon the Anticoagulant Properties of Dicumarol. Am. J. M. Sc. 210:634-637,1945. 9. Brambell, C. E.: Comments on the Value of Prothrombin Determinations. Blood Clotting and Allied Problems, Josiah Macy Jr. Foundation, New York, Tr. of the First Conference, Feb. 16-17, 1948, p. 99. 10. Von Sydow, G.: Hypoprothrombinemia and Cerebral Injury in Infant after Dicumarol Treatment of the Mother. Nord. med. 34:1171, 1947; abstracted in Vidabaek, A.: A Review of the Scan din avian Literature on Hematology from the Years 1946 to 1947. Acta. Haemat. 1:126, 1948. From Kraus, A. P., Perlow, S. and Singer, K., Danger of dicumarol treatment in pregnancy. J.A.M.A. 139:758-762, 1949. 11. Quick, A. J.: Experimentally Induced Changes in the Prothrombin Level of the Blood. J. BioI. Chem. 164:371, 1946. 12. Blood Clotting and Allied Problems, Appendix, Prothrombin Determinations Technique as Done in Various Laboratories. Josiah Macy, Jr. Foundation, New York, Tr. of the First Conference, Feb. 16-17, 1948. (a) Seegers, W. H.: Two Stage Prothrombin Determination, pp. 152-158. (b) Edsall, J. T.: Determination of Prothrombin in Plasma and Plasma Fractions, pp. 159-163. (c) Tocantins, L. M.: Prothrombin Determinations, pp. 164-165. (d) Barker, N. W.: Technique of the Quick Prothrombin Time as Performed at the Mayo Clinic, pp. 166-167. (e) Jaques, L. B.: Determinations of the Prothrombin Time, pp. 168-169. (j) Quick, A. J.: The Determination of Prothrombin by the Method of Quick, pp. 170-172. (g) Brambell, C. E.: Prothrombin Clotting Time Determination, Mercy Hospital Modification of Quick's Procedure, pp. 173-175. (h) Overman, R. S.: Method for the Determination of Prothrombin Clotting Time, pp. 177-178. 13. Miller, R., Harvey, W. P. and Finch, C. A.: Antagonism of Dicumarol by Vitamin K preparations. New England J. Med. 242:211-215,1950. 14. James, D. F., Bennett, 1. L., Scheinberg, P. and Butler, J. J.: Clinical Studies on Dicumarol Hypoprothrombinemia and Vitamin K Preparations: 1. The Superiority of Vitamin Kl Oxide over Menadione Sodium Bisulfite U .S.P. and Synkayvite in Reversing Dicumarol Hypoprothrombinemia. Arch. Int. Med. 83:632-652, 1949. 15. Phelps, E. T. and Jones, S. N.: Dicumarol Induced Hypoprothrombinemia Treated with Synkayvite, Vitamin Kl and Vitamin Kl Oxide. Paper given before the District of Columbia Chapter, American Federation for Clinical Research, May 19, 1950. To be published. 16. London, R. E.: Dicumarol Fatality in Sever Hypertensive and Arteriosclerotic Cardiovascular Disease Despite Controlled Therapeutic Level. Circulation 1:1205-1208, 1950. 17. Overman, R. S., Stahlman, M. A. and Link, K. P.: Studies on Hemorrhagic Sweet Clover Disease; Effect of 2 Methyl-l,4 naphthoquinone and I-Ascorbic Acid upon Action of 3/3 Methylenebis (4-hydroxycorimarin) on Prothrombin Time of Rabbits. J. BioI. Chem. 145:155-162, 1942. 18. Rivers, C. D.: Dicumarol and Prothrombin, under Queries and Minor N Qtes. J.A.M.A. 137:666, 1948.
Several contraindications to the use of Dicumarol have gradually accumulated. Death or severe disability has followed use of the dmg in some of the conditions listed in Table 1. TABLE 1 CONTRAINDICATIONS TO THE USE OF DICUMAROL THERAPY
Absolute Subacute bacterial endocarditis Purpura and blood dyscrasias Brain or cord surgery Advanced liver disease Jaundice and impaired absorption of vitamin K Expectation of immediate surgery Advanced kidney disease Active gastrointestinal bleeding Large ulcerating lesions Exposure to severe trauma Lat~ in pregnancy Regional aneBthesias and blocks Inadequate laboratory facilities
Relative Lack of blood for transfusion Lack of Vitamin Kt or Kl oxide History of bleeding ulcer Injection therapy (deep) Emaciation and malnutrition Hypertension and arteriosclerosis Generalized capillary disease
From the Department of Medicine, Geotgetown University Hospital and Georgetown University School of Medicine, Washington, D. C. * Instructor in Medicine, Georgetown University School of Medicine; Visiting Physician, Georgetown University Hospital. 1791
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Absolute Contraindications. The use of Dicumarol without clinical or laboratory check of the patient cannot be too strongly condemned, and if the patient does not know that he is receiving a dangerous drug which may cause bleeding, the situation is even \vorse (see Cases I and II). Because of the nature of subacute bacterial endocarditis and the likelihood of cerebral emboli, bleeding within the brain may follow deficiency in coagulation mechanism. Dicumarol therapy is an added hazard. Seven deaths in patients with subacute bacterial endocarditis who were treated with Dicumarol have been collected. l Parenthetically, anticoagulants have not been found to benefit the course of subacute bacterial endocarditis treated with antibiotics or sulfonamides. One could expect the bleeding tendency of purpura to be dangerously potentiated by anticoagulant therapy; and many of the blood dyscrasias have overt or latent bleeding tendencies which one would expect Dicumarol to increase (see Case V). With a past history of purpura one would profit by performing a bleeding work-up, consisting of a tourniquet test, prothrombin, bleeding, clotting and clot retraction times and a platelet count before beginning therapy. At toxic levels Dicumarol causes abnormalities in the bleeding time and coagulation time as well as in prothrombin time (see Case V). Following brain or spinal cord surgery (also ophthalmologic and some kinds of plastic surgery) small collections of blood may have disastrous effect, and Dicumarol is inadvisable, though there is probably no greater tendency to bleed than in other random cases. Lumbar puncture and cisternal puncture are dangerous because they may result in bleeding into confined spaces, with damage to the nervous system. Severe bleeding in a large series of postoperative cases treated with Dicumarol occurred in 1.9 per cent and mild bleeding (epistaxis, hematuria, petechiae and ecchymoses) in 3.1 per cent of 1686 patients 3. Advanced liver disease frequently results in a fall in prothrombin production. Though the exact site of action of Dicumarol is not absolutely known to be upon the metabolism of vitamin K and the formation of prothrombin by the liver, Dicumarol in the usual therapeutic doses may cause a severe, prolonged drop in the prothrombin contentS but smaller doses may be used with great care. 7 Patients with cirrhosis (with or without esophageal varices or hemorrhoids), severe acute hepatitis, chronic hepatitis, obstructive jaundice, steatorrhea or sprue and severe malnutrition are poor subjects for Dicumarol therapy. Intestinal coliform bacteria which form vitamin K are inhibited in the intestinal tract by oral streptomycin, sulfonamides and probably aureomycin and chloramphenicol and terramycin. This may be an overlooked cause of the unexplained changes in sensitivity of patients to Dicumarol when taking sulfonamides or antibiotics over long periods of time. The site of degradation and excretion of Dicumarol is not known but
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advanced kidney damage may cause excess response to Dicumarol and is a contraindication to its use. 3 Immediate surgery is contraindicated after fall in the prothrombin content during Dicumarol therapy; but transfusion and the intravenous injection of suspensions of 1000 mg. of the vitamin KI aid in returning the prothrombin content to safe levels in six to twenty-four hours if dangerous depression is present and surgery needed. If immediate surgery is in prospect, the danger of postoperative hemorrhage and wound dehiscence is an obstacle to the use of Dicumarol. One of our patients died following thoracentesis, certainly a very minor procedure, done while the prothrombin level was diminished by Dicumarol (see Case IV). Gastrointestinal bleeding, if active, is an absolute contraindication to the use of Dicumarol since it has been found that even after vigorous therapy the patient may continue to bleed severely. Davidson's fatal case demonstrated the marked prolongation of coagulation time seen with severe hypoprothrombinemia in Dicumarol poisoning, 8 but in neither his nor AlIen's case3 was an active peptic ulcer present prior to institution of anticoagulant therapy, though there had been previous peptic ulcers in both. Ulcerating lesions of all kinds, unless small, must be serious deterrents to the use of anticoagulants; malignancies, deep burns, active and probably inactive ulcerative colitis, and even large chronic phlebitic ulcers must be evaluated carefully before instituting therapy. As an example a patient of Allen3 with metastatic carcinoma of the duodenum, despite adequate prothrombin control, died of gastrointestinal hemorrhage after operation. When there is likelihood of exposure to severe trauma, ambulatory therapy with Dicumarol should not be used (see Case II). Children, except those in well controlled pediatric wards, laborers, farmers and athletes are particularly subject to severe trauma, predisposing to severe hemorrhage from lacerations, ecchymoses or hematomas which may cause massive tissue breakdown, deformity or death. At this time mention should be made of the patients with venous thrombosis or arterial occlusion of the lower extremity, now so frequently treated with Dicumarol, who receive paravertebral lumbar sympathetic regional injections with alcohol or local anesthetics. Lilly 2 collected four such fatal c.J,ses in which very severe contiguous and distant hemorrhage occurred. Similarly, regional injections for tic doloreaux, brachial plexus block, sacral block, perineal block, intercostal block and others should be unuertaken with extreme caution if at all and spinal anesthesia is definitely contraindicated during Dicumarol therapy. Lilly also reported a patient in whom the combination of a skeletal traction with a Steinman pin and Dicumarol therapy resulted in dangerous and severe hemorrhage into the extremity. Another patient had permanent deformity and long disability following the injection of penicillin in the gluteal region during
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therapy. If injections must be given during Dicumarol therapy, smallbore needles and easily absorbable products should be used. Newborn, especially premature infants, have a low prothrombin content even though their mothers have normal or even elevated levels. 9 The use of Dicumarol in the mother before delivery may cause serious bleeding in the child and increase the dangers of cerebral and other hemorrhages. 1o Both Quickll and Kraus10 demonstrated that induction of experimental hemorrhagic sweet clover disease in pregnant animals could cause death of offspring in utero or soon after birth. Because the newborn lack intestinal bacteria to form vitamin K they are unusually sensitive to Dicumarol in the first few days of life. After approximately ten years of clinical experience with Dicumarol, the chief contraindication to its use is still the lack of adequate laboratory control, or the lack of proper clinical use of the laboratory results. "Adequate laboratory control" infers the daily checking of plasma prothrombin prior to ordering that day's dose of Dicumarol. It also means a prothrombin determination done by a well trained technician, able to very closely reproduce her results on successive determinations with the same plasma and thromboplastin preparation, under the direction of a clinical pathologist. Proper clinical use of prothrombin determinations is most severely hindered by widespread misinformation among physicians concerning multiplicity of prothrombin tests and their many variations. In addition, different experts set up very different standards for interpretation of their own and others' prothrombin tests of normal, dilute and Dicumarol plasmas. For example, the original Quick test is so designed that the normal prothrombin time is 11 to 12t seconds. The unknown prothrombin times are expressed in "prothrombin activity" as per cent of normal derived from a fixed hyperbolic curve obtained through determinations of the prothrombin time of certain dilutions of normal plasma.H But the experts differ widely in their thromboplastin source and extraction, and use different diluents for the plasma. These variations cause changes in the normal prothrombin dilution curve. The normal prothrombin time for undiluted plasma varies from 11 to 19 seconds with tests in common clinical use. However, a plasma with a prothrombin time of 19 seconds by the original Quick method would be reported as havin..; 30 per cent activity. The practical result is that a physician getting reports from several neighboring hospitals or laboratories may have reports on prothrombin determinations done by a two-stage method with and without the AC-globin refinement,l2b upon whole fresh venous blood ("bedside method"),llc or by the very numerous variations of Quick's method. Hence the clinician may receive data expressed in the wrong unitage for the test used (see our Case IV), or may receive the data in the correct unitage but order anticoagulant according to accepted standards for
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another test, which he may have been accustomed to using in a neighboring hospital. The result may be either dangerous hypoprothrombinemia or insufficient depression of the coagulation for prevention of thromboembolic disease. Relative Contraindications. Healed peptic ulcer patients have suffered activation of these ulcers with fatal results as already mentioned,3, 8 the cause of the reactivation being unknown. The danger of deep injection therapy such as in regional anesthesia and alcohol nerve block during Dicumarol therapy have been mentioned, but even smaller and less traumatic injections should be kept at a minimum. Hypertension and arteriosclerosis have been associated with four of the published reports of death from Dicumarol therapy.1, 16 It is proposed16 that hypertension and arteriosclerosis damage the vascular endothelium allowing diapedesis. Link17 feels very strongly that vitamin C is a protective agent during Dicumarol therapy to influence the degree and duration of hypoprothrombinemia and the capillary integrity in the rat, the rabbit and guinea pig. Vitamin P deficiency has been implicated in vascular disease so that both vitamin P and C may also play a part in the tendency of hypertensive and arteriosclerotic patient to hemorrhage. The aged also appear to be more sensitive to Dicumarol but this may be a result of their arteriosclerosis. At present blood or plasma transfusions and vitamin K are the only effective antagonists of severe poisoning with Dicumarol. Citrated banked blood as well as fresh blood and bank plasma are similarly effective but give only mild and transient rise in the prothrombin concentration when the deficiency is severe. Most of the patients who have died of Dicumarol poisoning were treated unsuccessfully with blood and large doses of water-soluble vitamin K preparations. The phytyl side chain found in the oil-soluble vitamins K1 and K1 oxide appears to be necessary for reversal of severe Dicumarol intoxication.7, 13. 14, 15, Deficiency of prothrombin occurring during impaired ingestion or absorption of vitamin K does, however, respond to the water-soluble vitamin K products. Patients probably should not receive Dicumarol unless, in addition to reliable prothrombin determinations, the hospital has vitamin KI (or vitamin KI oxide) and blood for transfusions for emergency treatment when severe bleeding results. ILLUSTRATIVE CASES CASI'; 1. A 54 year old white man entered Georgetown University Hospital in November 1949 because of extremely severe swelling of the side of his face and displacement of his tongue causing respiratory distress. Dicumarol, apparently in 100 mg. daily doses, had been started one month before, because of chest pain and an abnormal electrocardiogram. He rested at home while taking the anticoagulant, vitamins and sedatives. About one week before entry his gums began
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to bleed and he saw his dentist who probed without effect except to increase bleeding, finally necessitating tooth extraction. Almost immediately a large hematoma began to form in the floor of the mouth and in the left cheek, finally displacing the tongue backward and closing the eye. Family and personal history were irrelevant. Physical examination was normal except for the face, mouth and neck. The left eye was completely closed; the left side of the face was very full and reddishblue in color. Ecchymoses were present on buccal, gingival and palatal mucosa. The tongue was displaced to the right and posteriorly and a large soft clot was present in the oropharynx. Marked anemia (hematocrit 22), grossly bloody urine containing 3 plus albumin and tarry, guaiac-positive stool were found. The initial bleeding work-up disclosed no abnormalities other than a prothrombin content of less than 10 per cent. A repeat clotting time by the Lee-White method was sixteen minutes. Therapy consisted of 780 mg. of Synkayvite and 1000 cc. of whole blood. On the fifth day of hospitalization the patient's physician discharged him despite a prothrombin time of 45 seconds (less than 10 per cent:content). On three occasions the oral clot had required manual removal to prevent blockage of the airway.
Comment. A near fatality from Dicumarol therapy occurred because the prothrombin levels were not checked. Dental surgery was done despite a clinical bleeding tendency of very recent duration. Insufficient blood transfusions and no vitamin Kl were given, and finally the patient was discharged while still critically hypoprothrombinemic. CASE H. A 17 year old Negro youth was readmitted to Gallinger Municipal Hospital on January 10, 1949, with the history that he had been discharged two weeks before with the diagnosis of an acute myositis but without specific therapy. The second admission was for right flank pain and grossly bloody urine which followed an athletic injury. History of anticoagulant therapy could not be elicited. Emergency pyelography was suggestive of perirenal hemorrhage on the right side. Urinary bleeding increased during the first few hours of hospitalization and operation followed. A large perirenal hemorrhage was found. Severe oozing into the operative field could not be stopped and borderline shock developed. Prothrombin determinations taken while the patient was in surgery were prolonged to more than 70 seconds. Continuous whole blood transfusions were given along with 72 mg. of Synkayvite every four hours. On the second day 72 mg. of Synkayvite was given to a donor and twelve hours later 500 cc. of blood withdrawn to give to the patient; no apparent improvement resulted. After six days the prothrombin level rose to 30 per cent or more of normal and remained there, and bleeding stopped. On ward rounds on the seventh day a visiting physician, suspicious because of a similar case of his own, elicited the history that the boy had seen a doctor who prescribed pills for "a blood clot in the arm." Confirmation that 300 mg. of Dicumarol had been taken in the four days before admission was obtained. He was discharged on February 4,1949.
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Comment. Since the use of Dicumarol has become so widespread and somewhat indiscriminate, careful questioning regarding Dicumarol therapy is necessary in all unusual bleeding cases. A near fatality and unnecessary surgery occurred because the patient was not told about his therapy. A prothrombin determination and possibly a complete bleeding work-up may be necessary in such cases, and surgical procedures should not be performed without corrective therapy with blood transfusions and vitamin K 1. Ambulatory therapy with Dicumarol should not be used without a preceding period of hospitalization for dosage regulation. Patients should be told of the nature and dangers of their therapy. CASE Ill. A 46 year old white single man entered Georgetown University Hospital on January 27, 1950 because of recurrent substernal pain of eleven days' duration. The electrocardiogram revealed evidence of recent myocardial infarction and Dicumarol was started. The patient's physician made daily prothrombin determinations in his own downtown laboratory and prescribed Dicumarol based on his prothrombin determinations, which indicated that the patient was "resistant" to Dicumarol. On the twenty-eighth hospital day the patient had a severe nosebleed which could not be stanched. This was after a total dose of 4800 mg. of Dicumarol, and with a prothrombin of 21.6 seconds (23 per cent content) (modified Quick method) by the physician's laboratory. The prothrombin by the Georgetown University Hospital Clinical Laboratory was 40.3 seconds (less than 10 per cent content) (modified Quick method). Ten milligrams of Synkayvite and 72 mg. of menadione sodium bisulfite U.S.P. were given. Gradually diminishing bleeding (total loss of 500 cc.) occurred for four days, during part of which time the patient refused to sleep because he feared he would bleed and drown in blood. The prothrombin content remained less than 30 per cent for four days after the first bleeding, and returned to normal on the fifth day
Comment. A dangerously low prothrombin content and hemorrhage resulted after almost one month of Dicumarol dosage which averaged about twice the usual daily dose because of apparent insensitivity. Exchange of views on details of prothrombin determination among the laboratories in a natural geographical area, such as Washington, D.e. and suburbs, might obviate tragic errors. Standardization of technic and a system of mutual checking could be initiated. A necessary factor would be a common source for a preparation of thromboplastin. In contrast to some laboratory procedures where a 10 per cent error is inconsequential, such an' error in prothrombin might cause death from pulmonary emboli by use of too little Dicumarol or death from hemorrhage through use of too much. CASE IV. An elderly white man was admitted to a hospital in late 1949 because of abdominal pain and shortness of breath. The signs of hypertensive
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cardiovascular disease, cardiac decompensation, myocardial infarction and left hydrothorax were found on hospitalization. Several thoracenteses disclosed a yellowish nonbloody fluid prior to Dicumarol therapy. Dicumarol was begun on the ninth hospital day and was continued for fifteen days, the total dose being 1300 mg. The longest prothrombin times recorded were 76.8 seconds on the tenth day of Dicumarol therapy and 96 seconds nineteen days after the onset of therapy. A Dicumarol therapy sheet was used which gave the control prothrombin time, the patient's prothrombin time, the dose of Dicumarol and the graphic per cent of normal prothrombin time. The latter was calculated by dividing the control prothrombin in seconds by the patient's prothrombin in seconds. Because fluid reaccumulated in the left chest thoracenteses were done after Dicumarol was started, bloody fluid being obtained. Twenty-seven days after admission and eighteen days after beginning Dicumarol the patient expired with signs of shock and left hemothorax despite several transfusions and 144 mg. of Hykinone intravenously. Thoracentesis just before death gave "1200 cc. of blood." Postmorten examination was performed.
Comment. The laboratory error in reporting the prothrombin by dividing the normal or control time by the patient's time was out of line with the prothrombin time in seconds and could have been spotted. This is a very common error and may be one reason for serious bleeding in patients with recorded prothrombin levels above 30 per cent.'S In the bedside whole blood method of Smith the patient's prothrombin is, however, calculated just this way, further indicating the need for standardization of procedures and nomenclature. Thoracentesis probably should not have been done during the Dicumarol therapy. A single standard laboratory procedure is a present necessity for safe Dicumarol therapy. CASE V. A 68 year old widow entered Georgetown University Hospital in April 1950 because of painless and later very painful hematuria of one day's duration. Four weeks before admission she had developed a phlebothrombosis of the leg and was placed on Dicumarol in doses of 200 mg. the first, 100 mg. the second, and 50 mg. daily maintenance. Prothrombin time had been within therapeutic range on checking it every two days in a clinical laboratory until the drug was stopped. The drug was stopped seven days prior to admission. Watersoluble vitamin K given at home had no apparent effect. The patient had always bruised easily but had never been troubled by it. Examination showed many petechiae over the legs and an ecchymoses on the left thumb and right arm. Bleeding work-up showed a prothrombin content of less than 10 per cent, platelet count of 68,000, clotting time of twenty minutes and 4 seconds, bleeding time of seven minutes and 55 seconds, positive RumpelLeed test and diminished clot retraction. Marked hematuria and albuminuria were present. Severe bilateral renal colic developed despite intravenous Hykinone 72 mg. every three hours for twenty-four hours, and 1000 cc. of whole blood. After receiving 1000 mg. of vitamin K, suspension intravenously, the prothrombin rose to 66 per cent content and renal colic subsided. However, six days later
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severe right renal colic recurred and the prothrombin determination showed 33 per cent content (modified Quick method). An additional 1000 mg. of vitamin KI intmvenously was given and the prothrombin level rose to 57 per cent content without further relapse. A pyelogram done later was normal. A platelet count of 56,000 was found after the bleeding tendency had stopped.
Comment. Ambulatory use of Dicumarol without previous standardization of dosage in the hospital is dangerous. Sudden changes in sensitivity or response to the drug are recorded in the literatUre. Hematuria and renal colic in patients receiving Dicumarol should be a tip-off to watch closely and check prothrombin levels. The history of easy bruising is not an unusual one but perhaps should have stimulated a test of bleeding tendencies before therapy, though a platelet count of 60,000 is usually not accompanied by purpura or diminished clot retraction. SUMMARY AND CONCLUSIONS
Contraindications to the use of Dicumarol have been presented with some illustrative case reports from several hospitals in a representative community. The dangers of Dicumarol therapy are at least partially the result of the use of a very potent drug whose dosage depends on a test, the prothrombin determination, which is at present insufficiently standardized in the clinical laboratories and insufficiently understood by many physicians. The physician who knows the contraindications to Dicumarol therapy, the specific prothrombin test used on his patients, the correct therapeutic range and controls the drug dosage to attain the proper level will rarely encounter dangerous bleeding. If the prothrombin results are out of line with clinical appearance the clinician should check with the laboratory where he may find errors in technic and terminology. Standardization of thromboplastins, prothrombin determinations and terminology on a local basis may obviate deaths and disability from errors in Dicumarol therapy. REFERENCES 1. Duff, 1. F. and Shull, W. H.: Fatal Hemorrhage in Dicumarol Poisoning. J.A.M.A. 139:762-766, 1949.
2. Lilly, G. D. and Lee, R. M.: Complications of Anticoagulant Therapy. ,Surgery 26:957-967,1949. 3. Allen, E. V.: The Clinical Use of Anticoagulants, Report of Treatment with Dicumarol in 1,686 Postoperative Cases. J.A.M.A. 134:323-329, 1947.
4. Wright, 1. S., Marple, C. D. and Beck, D. F.: Anticoagulant Therapy of Coronary Thrombosis with Myocardial Infarction. J.A.M.A. 138:10741079, 1948 ..
5. Link, K. P.: Dicumarol-and the Estimation of Prothrombin, or "The
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World, The Flesh and/or the Devil." Blood Clotting and Allied Problems, Josiah Macy, Jr. Foundation, New York, Tr. of the First Conference Feb. 16-17, 1948, p. 130. 6. Reisner, E. H., Norman, J., Field, W. W. and Brown, R.: The Effect of Liver Dysfunction on the Response to Dicumarol. J. Clin. Investigation 28:445-447, 1949. 7. Harvey, W. P. and Finch, C. A.: Dicumarol Prophylaxis of Thromboembolic Disease in Congestive Heart Failure. New England J. Med. 242:208-211, 1950. 8. Davidson, C. S., Freed, J. H. and MacDonald, H.: The Effect of Vitamin Kl Oxide Upon the Anticoagulant Properties of Dicumarol. Am. J. M. Sc. 210:634-637,1945. 9. Brambell, C. E.: Comments on the Value of Prothrombin Determinations. Blood Clotting and Allied Problems, Josiah Macy Jr. Foundation, New York, Tr. of the First Conference, Feb. 16-17, 1948, p. 99. 10. Von Sydow, G.: Hypoprothrombinemia and Cerebral Injury in Infant after Dicumarol Treatment of the Mother. Nord. med. 34:1171, 1947; abstracted in Vidabaek, A.: A Review of the Scan din avian Literature on Hematology from the Years 1946 to 1947. Acta. Haemat. 1:126, 1948. From Kraus, A. P., Perlow, S. and Singer, K., Danger of dicumarol treatment in pregnancy. J.A.M.A. 139:758-762, 1949. 11. Quick, A. J.: Experimentally Induced Changes in the Prothrombin Level of the Blood. J. BioI. Chem. 164:371, 1946. 12. Blood Clotting and Allied Problems, Appendix, Prothrombin Determinations Technique as Done in Various Laboratories. Josiah Macy, Jr. Foundation, New York, Tr. of the First Conference, Feb. 16-17, 1948. (a) Seegers, W. H.: Two Stage Prothrombin Determination, pp. 152-158. (b) Edsall, J. T.: Determination of Prothrombin in Plasma and Plasma Fractions, pp. 159-163. (c) Tocantins, L. M.: Prothrombin Determinations, pp. 164-165. (d) Barker, N. W.: Technique of the Quick Prothrombin Time as Performed at the Mayo Clinic, pp. 166-167. (e) Jaques, L. B.: Determinations of the Prothrombin Time, pp. 168-169. (j) Quick, A. J.: The Determination of Prothrombin by the Method of Quick, pp. 170-172. (g) Brambell, C. E.: Prothrombin Clotting Time Determination, Mercy Hospital Modification of Quick's Procedure, pp. 173-175. (h) Overman, R. S.: Method for the Determination of Prothrombin Clotting Time, pp. 177-178. 13. Miller, R., Harvey, W. P. and Finch, C. A.: Antagonism of Dicumarol by Vitamin K preparations. New England J. Med. 242:211-215,1950. 14. James, D. F., Bennett, 1. L., Scheinberg, P. and Butler, J. J.: Clinical Studies on Dicumarol Hypoprothrombinemia and Vitamin K Preparations: 1. The Superiority of Vitamin Kl Oxide over Menadione Sodium Bisulfite U .S.P. and Synkayvite in Reversing Dicumarol Hypoprothrombinemia. Arch. Int. Med. 83:632-652, 1949. 15. Phelps, E. T. and Jones, S. N.: Dicumarol Induced Hypoprothrombinemia Treated with Synkayvite, Vitamin Kl and Vitamin Kl Oxide. Paper given before the District of Columbia Chapter, American Federation for Clinical Research, May 19, 1950. To be published. 16. London, R. E.: Dicumarol Fatality in Sever Hypertensive and Arteriosclerotic Cardiovascular Disease Despite Controlled Therapeutic Level. Circulation 1:1205-1208, 1950. 17. Overman, R. S., Stahlman, M. A. and Link, K. P.: Studies on Hemorrhagic Sweet Clover Disease; Effect of 2 Methyl-l,4 naphthoquinone and I-Ascorbic Acid upon Action of 3/3 Methylenebis (4-hydroxycorimarin) on Prothrombin Time of Rabbits. J. BioI. Chem. 145:155-162, 1942. 18. Rivers, C. D.: Dicumarol and Prothrombin, under Queries and Minor N Qtes. J.A.M.A. 137:666, 1948.