Caldwell, M. June

Johnson, Shirley A.

Priest, Edward McCall

English

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Henry Ford Hospital Medical JournalVolume 4 | Number 4 Article 512-1956The Effect Of The Administration Of TheAnticoagulant Marcumar On The BloodCoagulation MechanismsShirley A. JohnsonM. June CaldwellEdward McCall PriestFollow this and additional works at: https://scholarlycommons.henryford.com/hfhmedjournalPart of the Life Sciences Commons, Medical Specialties Commons, and the Public HealthCommonsThis Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in HenryFord Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. For more information, please contactacabrer4@hfhs.org.Recommended CitationJohnson, Shirley A.; Caldwell, M. June; and Priest, Edward McCall (1956) "The Effect Of The Administration Of The AnticoagulantMarcumar On The Blood Coagulation Mechanisms," Henry Ford Hospital Medical Bulletin : Vol. 4 : No. 4 , 224-227.Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol4/iss4/5THE EFFECT OF THE ADMINISTRATION OF THE ANTICOAGULANT MARCUMAR ON THE BLOOD COAGULATION MECHANISMS SHIRLEY A. JOHNSON, Ph. D.*, M . JUNE CALDWELL, B.A. AND EDWARD M C C A L L PRIEST, M.D.** The coumarin type anticoagulants are considered to decrease the plasma levels of prothrombin and of one other plasma protein related to the coagulation mechanisms, autoprothrombin I (factor V I I ) \ Autoprothrombin I is believed to drop under the influence of these drugs before the prothrombin levels begin to fall. However, the time lag between the changes of each factor varies with the anticoagulant. Recently, however, Verstraete 1954^ Sise, Kimball and Adamis 1955^ and Johnson and Seegers 1955^ reported a decrease in the plasma levels of autoprothrombin I I (Christmas factor, Plasma Thromboplastin Component) following the administration of some of these anticoagulants. Therapeutic anticoagulant administration is controlled by the Quick one-stage prothrombin time. This test is influenced by two of the three factors which we know the anticoagulants alter, but not by all three. There is no known test that will measure changes in all three factors simultaneously with any appreciable accuracy. The Quick prothrombin time is still probably the single, most useful, test to use. Nevertheless, hemorrhage has been observed in patients with a prothrombin time reduction to only 30-40 per cent of normal according to the Quick test. This discrepancy between laboratory findings in anticoagulant control and clinical observations could be due, at least in part, to changes in plasma levels of autoprothrombin I I which are not observed in the laboratory using this one routine test. An effective anticoagulant, which does not affect the plasma levels of autopro-thrombin I I , might well be the safest and easiest anticoagulant to control. Marcumar is an effective anticoagulant. Control of anticoagulant effect by marcumar is noticeably smoother than with other anticoagulants. This characteristic suggested an absence of effect on autoprothrombin I I and led to this present investigation. The role of the various factors which influence the Quick prothrombin time, in thrombotic disease, has not been fully delineated. It is possible that while the levels of two factors are measured usually during anticoagulant therapy, the beneficial effect *Department of Laboratories. ** Division of Cardiology. 224 of the therapy may be due to the reduction or change in the level of yet another factor. The results reported here do give us some understanding of the ease of control of one drug by the usual laboratory procedures. METHODS The methods used in this study have been described elsewhere, and are only briefly mentioned here. One-stage prothrombin time: This method was described by Quick^ Two-stage prothrombin determination: Ware and Seegers described this test modified from that of Warner, Brinkhous and Smith'. Two-stage autoprothrombin I test: This test was developed by Seegers, Johnson and Penner'. Two-stage autoprothormbin I I test: This test was first described by Johnson and Seegers'. RESULTS THE PLASMA PROTHROMBIN LEVELS: In about half of the patients followed under Marcumar therapy, the two-stage prothrombin values did not change during the first twenty-four hours of therapy. However, in all ten patients the prothrombin values had dropped on the second day, and all had fallen by the fourth day to 50 u/ml. or below. THE AUTOPROTHROMBIN I I LEVELS: Unlike the anticoagulants studied previously Marcumar does not reduce the plasma and serum levels of autoprothrombin I I . The cases were followed for at least fifteen days, and in some cases as long as twenty-eight days and the autoprothrombin I I levels remained the same throughout. There is considerable variation in these levels before therapy. In one case, with myocardial infarction, no autoprothrombin I I was found in the serum before therapy began. THE AUTOPROTHROMBIN I LEVELS: These levels fell in the first day in every case. The fall in autoprothrombin I alwavs preceded the fall in prothrombin or coincided with it. As has always been the case, the values for this factor were found to be higher in serum than in plasma. 225 DISCUSSION Since Marcumar has been found to decrease the plasma levels of autoprothrombin I and prothrombin, but not autoprothrombin I I , the significance of this latter component in the treatment of thrombosis can be considered. It is known that autoprothrombin I I is deficient in patients with hemophilia B'"". One of our patients sustained a myocardial infarction in the face of an absence of autoprothrombin I I . There was no history of hemorrhagic tendency in this case. The anticoagulants Dicumarol, Hedulin, Tromexan and Sintrom all may reduce the autoprothrombin I I level to practically zero without patient hemorrhage'^ Conversely, patients may hemorrhage when the determined prothrombin time is not sufficiently reduced to account for this, and it has been postulated that a reduction of autoprothrombin I I may be the explanation for this undesirable effect. Marcumar produces a reasonably stable anticoagulant effect as measured by the Quick prothrombin time. This observation is enhanced by clinical experience". Numerous reports attest to Marcumar as an effective anticoagulant'"''^.". Since autoprothrombin I I is not reduced by this drug, it is possible that its reduction is not necessary for effective anticoagulation therapy. There is another consideration to bear in mind. It has been suggested by O'Brien that autoprothrombin I I may have a prosthetic group which is phospholipid in nature". This offers a possible connection between the lipids of blood and the coagulant mechanisms in the problem of thrombosis. The part played by this factor autoprothrom-bin I I on the thrombosing tendency is very obscure and difficult to evaluate. Consider-ably more time will need to elapse, in all probability, before the study is complete. CONCLUSIONS The changes in the plasma levels of the pertinent components in the blood coagulation mechanisms have been studied in conjunction with the administration of the anticoagulant, Marcumar. This drug, Marcumar, does not alter the plasma levels of autoprothrombin I I (PTC, Christmas factor) as does Dicumarol, Tromexan, Hedulin or Sintrom. The findings may account for the observation that anticoagulant therapy can be easily controlled with Marcumar as the Quick prothrombin time is the commonly used laboratory test under these circumstances, and this test is not influenced bv different levels of autoprothrombin I I . The concepts involving autoprothrombin I I in the formation of intravascular thrombosis are viewed. BIBLIOGRAPHY 1. Mann, F. D.: Co-thromboplastin assay; means of study of abnormalities of blood coagu-lation. Am. J. Clin. Path. 19:861, 1949. 2. Verstraete, M. : La formation de la thromboplastine plasmatique; etude du syndrome hemophilique, Bruxelles, Arscia, 1955. 226 3. Sise, H. S., Kimball, D. M., and Adamis, D.: Plasma thromboplastin component (PTC) deficiency produced by prolonged administrations of prothrombopenic anticoagulants, Proc. Soc. Exper. Biol. & Med. 89:81, 1955. 4. Johnson, S. A. and Seegers, W. H.: Reduction of autoprothrombin I I . Activity with dicumarol. Circulation Res. 4:182, 1956. 5. Quick, A. J.: Nature of bleeding in jaundice, J.A.M.A. 110:1658, 1938. 6. Ware, A. G., and Seegers, W. H.: Two-stage procedure for the quantitative determination of prothrombin concentration. Am. J. Clin. Path. 19:471, 1949. 7. Warner, E, D., Brinkhous, K. M., and Smith, H. P.: Quantitative study on blood clotting, prothrombin fluctuations under experimental conditions. Am. J. Physiol. 114:667, 1936. 8. Seegers, W. H., Johnson, S. A., and Penner, J. A.: Quantitative concepts related to prothrombin and autoprothrombin I . Activity, Canad. J. Biochem. Physiol. 34:887, 1956. 9. Johnson, S. A., and Seegars, W. H.: Use of purified prothrombin in the study of hemophilia and plasma thromboplastin component (PTC) deficiency, J. Appl. Physiol. 6:429, 1954. 10. Biggs, R., and others: Christmas disease; condition previously mistaken for haemophilia. Brit. M . J. 2:1378, 1952. 11. Aggeler, P. M., and others: Plasma thromboplastin component (PTC) deficiency; new disease resembling hemophilia, Proc. Soc. Exper. Biol. & Med. 79:692, 1952. 12. Johnson, S. A. Seegers, W. H., Koppel, J. L. and Olwin, J. H.: The reduction of platelet cefaclor II (Autoprothrombin II) activity with anticoagulants. In press. 13. Priest, E. M.: Unpublished observations. 14. Brambel, C. E., and Serra, G. L.: Oral anticoagulant therapy and its control: Phenpro-coumon; a new highly active anticoagulant and phytomenadione as an effective regulator, Abst. In Internat. Soc. Hematol. VI Congress, p. 379, 1956. 15. Bourgain, R., Todd, M., Herzig, L., and Wright, I . S.: Marcumar •[3-( T-phenyl-propyl) -4-hydroxycoumarin]; a new anticoagulant. Circulation 10:680, 1954. 16. Roller, Von F., and Jakob, H.: Ueber ein neues, hochaklives Antikoagulans mit pro-irahierter Wirkung (Marcoumar), Schweiz. med. Wchnschr. 83:476, 1953. 17. O'Brien, J.: Effect of cobra venom and bee venom on plasma, Abst. In Internat. Soc. Hematol. VI Congress, p. 332, 1956. 227 

The Effect Of The Administration Of The Anticoagulant Marcumar On The Blood Coagulation Mechanisms

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The Effect Of The Administration Of The Anticoagulant Marcumar On The Blood Coagulation Mechanisms

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