Metabolism of the Coagulation Factors of the Prothrombin Complex in Hypothyroidism in Man

Summary

The metabolic rate of prothrombin, factors VII, IX and X, was studied in nine hypothyroid patients. Disappearance rates of the four vitamin-K-dependent factors, called the prothrombin complex, were measured after assumedly complete blocking of their synthesis with adequate doses of a coumarin congener (acenocoumarol). Reappearance rates were assessed by induction of synthesis with high doses of vitamin K₁ (phytomenadion) when stable hypocoagulability had been achieved. Normal values for these rates were derived from earlier studies in our laboratory. In hypothyroid patients the rates of both disappearance and reappearance were significantly slower for all factors tested. Practical consequences of these observations are discussed.

The initial level of factor-IX activity in all nine patients was substantially lower than in normal individuals. Therapy by thyroxine-substitution led to normal levels of factor-IX. This implies a divergency in the retardation of the breakdown and production rates in hypothyroidism. The reappearance rate was indeed found to be more retarded than the disappearance rate.

• References

• 1 Biggs R, Denson KW E. 1963; The fate of prothrombin and factors VIII, IX, and X transfused to patients deficient in these factors. British Journal of Haematology 9: 532
• 2 Borchgrevink CF, Egeberg O, Pool JG, Skulason T, Stormorken H, Waaler B. 1959; A study of a case of congenital hypoprothrombinaemia. British Journal of Haematology 5: 294
• 3 Bowie EJ W, Thompson JH, Didisheim P, Owen CA. 1967; Disappearance rates of coagulation factors: Transfusion studies in factor-deficient patients. Transfusion 7: 174
• 4 Brown CH, Kvols LK, Tah-Hsiung HS U, Levin J. 1972; Factor IX deficiency and bleeding in a patient with Sheehan’s syndrome. Blood 39: 650
• 5 Egeberg O. 1963; Influence of thyroid function on the blood clotting system. Scandinavian Journal of Clinical and Laboratory Investigation 15: 1
• 6 Esch B, Van Der. 1960; De werking van coumarine preparaten op de bloedstolling bij hoge initiele dosering. Versing van de derde conferentie van de Thrombosediensten van het Nederlandsche Roode Kruis 26
• 7 Graham JB. 1960; Stuart clotting defect and Stuart factor. Thrombosis et Diathesis Haemorrhagica 4 (suppl.) 22
• 8 Hasselback R, Hjort PF. 1960; Effect of heparin on in vivo turnover of clotting factors. Journal of Applied Physiology 15: 945
• 9 Hellemans J, Vorlat M, Verstraete M. 1963; Survival time of prothrombin and factors VII, IX and X after completely synthesis blocking doses of coumarin derivatives. British Journal of Haematology 9: 506
• 10 Hermens WTH. 1975. Dose calculation of human factor-VIII and factor-IX concentrates for infusion therapy. In: Brinkhous KM, Hemker HC. (eds.) Handbook of Hemophilia. Excerpta Medica; Amsterdam: p 569
• 11 Httzig W, Von H, Zollinger W. 1958; Kongenitaler Faktor-VII-Mangel. Helvetica Paediatrica Acta 13: 189
• 12 Hjort PF, Egeberg O, Mikkelsen S. 1961; Turnover of prothrombin, factor VII and factor IX in a patient with hemophilia A. Scandinavian Journal of Clinical and Laboratory Investigation 13: 668
• 13 Hoag MS, Aggeler PM, Fowell AH. 1960; Disappearance rate of concentrated proconvertin extracts in congenital and acquired hypoproconvertinemia. Journal of Clinical Investigation 39: 554
• 14 Ikkala E, Eisalo A, Heinivaara O. 1962; Plasma coagulation factors in thyrotoxicosis. Acta Endocrinologica 40: 307
• 15 Kazmier FJ. 1966. Effect of oral anticoagulants on factors VII, IX, X and II. Thesis. University of Minnesota:
• 16 Kazmier FJ. 1974; Current practice with vitamin K antagonist therapy. Mayo Clinic Proceedings 49: 918
• 17 Kazmier FJ, Spittell JA, Thompson JJ, Owen CA. 1965; Effect of oral anticoagulants on factors VII, IX, X, and II. Archives of Internal Medicine 115: 667
• 18 Loeliger EA, Esch BV D, Ter Haar Rombny-Wachter CC H, Boou HL. 1960; Factor VII: its turnover rate and its possible role in thrombogenesis. Thrombosis et Diathesis Haemorrhagica 4: 196
• 19 Loeliger EA, Van Dar EschB, Mattern MJ, Hemker HC. 1964; The biological disappearance rate of prothrombin, factors VII, IX, and X from plasma in hypothyroidism, hyperthyroidism, and during fever. Thrombosis et Diathesis Haemorrhagica 10: 267
• 20 Loeliger EA, Hensen A. 1961; Substitution therapy in haemophilia B. Thrombosis et Diathesis Haemorrhagica 6: 391
• 21 Van Dar MeerJ, Hemker HC, Loeliger EA. 1968; Pharmacological aspects of vitamin K₁ . Thrombosis et Diathesis Haemorrhagica suppl 29
• 22 Oosterom AT, Van MattieH, Hermens WT H, Veltkamp JJ. 1976; The influence of the thyroid function on the metabolic rate of prothrombin, factor VII and factor X in the rat. Thrombosis and Haemostasis 35: 607
• 23 O’reilly RA, Aggeler PM. 1970; Determinants of the response to oral anticoagulant drugs in man. Pharmacological Reviews 22: 35
• 24 O’reilly RA, Aggeler PM, Hoag MS, Loeng LS, Kropatkin ML. 1964; Hereditary transmission of exceptional resistance to coumarin anticoagulant drugs. New England Journal of Medicine 271: 809
• 25 Pyörälä K. 1965; Determinants of the clotting factor response to warfarin in the rat. Annales Medicinae Experimentalis et Biologiae Fenniae. 43 suppl 3
• 26 Rice AJ, Mcintosh TJ, Fouts FR, Brunk SF, Wilson WR. 1971; Decreased sensitivity to warfarin in patients with myxedema. American Journal of Medical Sciences 262: 211
• 27 Simone JV, Abildgaard CF, Schulman I. 1965; Blood coagulation in thyroid dysfunction. New England Journal of Medicine 273: 1057
• 28 Taylor AL, Finster JL, Mintz DH. 1969; Metabolic clearance and production rates of human growth hormone. Journal of Clinical Investigation 48: 2349
• 29 Veltkamp JJ, Drion EF, Loeliger EA. 1968; Detection of the carrier state in hereditary coagulation disorders I. Thrombosis et Diathesis Haemorrhagica 19: 279
• 30 Wagner JG. 1971. Biopharmaceutics and relevant pharmacokinetics Hamilton, III. Drug Intelligence Publications;