“COMPLICATED MIGRAINE” ITS ASSOCIATION WITH INCREASED PLATELET AGGREGABILITY AND ABNORMAL PLASMA COAGULATION FACTORS

The reasons for the prolonged and selective focal cerebral ischemia in complicated migraine remain to be clarified. The results of this study of coagulation mechanisms suggest that small thromboemboli may further compromise the cerebral perfusion in migraine. Platelet aggregability to ADP, epinephrine and serotonin was studied in seven patients with complicated migraine 2 weeks to 1 year after an episode of focal cerebral dysfunction. In addition, twelve patients who had uncomplicated migraine were also studied in between headaches. The patients with complicated migraine also had, during the acute stage of their focal cerebral ischemic episode, a detailed analysis of plasma factors that promote and inhibit coagulation. Each of the clotting abnormalities tended to correlate with the neurological outcome of the ischemic episode: 1. Patients with the most hyperaggregable platelets, but normal plasma coagulation factors had many transient episodes dating from childhood and early adolescence, compatible with fragile, white platelet thrombi. 2. Patients with dual coagulation abnormalities presented with a completed stroke as one of their first episodes of focal cerebral dysfunction, and they did so significantly later in life, after they had had many uncomplicated migraine attacks. Their platelets were no more hyperaggregable than those of many patients with uncomplicated migraine. It is therefore postulated that the decisive new element was the plasma hypercoaguability. Most of these patients had taken estrogens for many months, but not necessarily immediately before their stroke. Their family history was strongly positive for conditions predisposing to early disease of the vessel wall. Such conditions were absent in relatives of the patients with complicated migraine who had normal plasma coagulation factors. The high incidence of platelet hyperaggregability in these series of patients with complicated and uncomplicated migraine is discussed. The direct and indirect effects of estrogens on coagulation mechanisms are noted. In these patients, complicated migraine appears to be an association of the genetic disorder migraine together with platelet, plasma, or vessel wall abnormalities which may accentuate the ischemic process. REFERENCES 1. Brendshaw, P., and Parsons, M.: Hemiplegic migraine, a clinical study, Quart. J. Med., 34:65, 1965. 2. Whitty, C. W. M.: Familial hemiplegic migraine, J. Neurol. Neurosurg. Psychiat., 16:172, 1953. 3. Bickerstaff, E. R.: Basilar artery migraine, Lancet, 1:15, 1961. 4. Rosenbaum, H. E.: Familial hemiplegic migraine, Neurol., 10:164, 1960. 5. Simard, D., and Paulson, O. B.: Cerebral vasomotor paralysis during migraine attack, Arch. Neurol., 29:207, 1973. 6. O'Brien, M. D.: Cerebral blood changes in migraine, Headache, 10:139, 1971. 7. Skinhøj, E., and Paulson, O. B.: Regional blood flow in internal carotid distribution during migraine attack, Brit. Med. J., 3: 569, 1969. 8. Caroll, J. D.: Migraine, its variants, differential diagnosis and treatment, Res. Clin. Stud. Head., 1:46, 1967. 9. Whitty, C. W. M.: Migraine without headache, Lancet, 2:283, 1967. 10. Pearce, J. M. S., and Foster, J. B.: An investigation of complicated migraine, Neurol., 15:333, 1965. 11. Kalendovsky, Z., Austin, J., and Steele, P.: Increased platelet aggregability in young patients with stroke, [In press.] Arch. Neurol., 32:13, 1975. 12. Connor, R. C. R.: Complicated migraine. A study of permanent neurological and visual defects caused by migraine, Lancet, 2: 1072, 1962. 13. Guest, I. A., and Woolf, A. L.: Fatal infarction of brain in migraine, Brit. Med. J., 1:225, 1964. 14. Gardner, J. H., Hornstein, S., and van den Noort, S.: The clinical characteristics of headache during impending cerebral infarction in women taking oral contraceptives, Headache, 8:108, 1968. 15. Mustard, J. F., Jørgenson, L., and Hovig, T.: Role of platelets in thrombosis, Thromb. Diath. Haemorh. Suppl., 21:131, 1966. 16. Steele, P. P, Weily, H. S., and Genton, E.: Platelet survival and adhesiveness in recurrent venous thrombosis, N.E.J.M., 288:1148, 1973. 17. von Kaulla, E., von Kaulla, K. N, and Droegemueller, W.: Clinical hypercoagulability and oral contraceptives, Rocky Mount. Med. J., 69:33, 1971. 18. Whitty, C. W. M., Hockaday, J. M., and Whitty, M. M.: The effect of oral contraceptives on migraine, Lancet, 1:856, 1966. 19. Sicuteri, F., Del Bianco, P. L., and Anselmi, B.: Migraine as a cyclic disease with latent and overt components3/4effects with an antaminic drug, Headache, 10:53, 1970. 20. Sicuteri, F., Buffoni, F., Anselmi, B., and Del Bianco, P. L.: An enzyme (MAO) defect on the platelets in migraine. Res. Clin. Stud. Head., 3:245, 1972. 21. Smith, I., Kellow, A. H., Mullen, P. E., and Hanington, E.: Dietary migraine and thyramine metabolism, Nature, 230:246, 1971. 22. Hilton, B. P., and Cumings, J. N.: 5-hydroxytryptamine levels and platelet aggregation responses in subjects with acute migraine headache, J. Neurol. Neurosurg. Psychiat., 35:505, 1972. 23. Curzon, G., Barrie, M., and Wilkinson, M. I. P.: Relationship between headache and amine changes after administration of reserpine to migrainous patients, J. Neurol. Neurosurg. Psychiat., 32:555, 1969. 24. Ad Hoc Committee on Classification of Headache: Classification of headache, J.A. M.A., 179:717, 1962. 25. Mettler, L., and Selchow, B. M.: Oral contraceptives and platelet function, Thromb. Diath. Haemorh., 28:213, 1972. 26. Masi, A. T., and Dugdale, M.: Cerebrovascular diseases associated with the use of oral contraceptives. A review of English-language literature, Ann Int. Med., 72:111, 1970. 27. Swank, R. L., and Davis, E.: Blood cell aggregation and screen filtration pressure, Circul., 33:617, 1966. 28. Dhall, P. D., Engeset, J., McKenzie, F. N., and Matheson, N. A.: Screen filtration pressure of blood, an evaluation, Cardiovasc. Res., 3:147, 1969. 29. Swank, R. L.: The screen filtration pressure method in platelet research. Significance and interpretation, Set. Haemat., 1:146, 1968. 30. Eika, C.: Platelet refractory state induced by heparin, Scand. J. Haemat., 9:665, 1972. 31. Lees, F., and Watkins, S. M.: Loss of consciousness in migraine, Lancet, 2:647, 1963. 32. Beck, U., and Manz, F.: Kindliche und juvenile focale migraine, Arch. Pschiat. Nervenkr., 215:407, 1972. 33. Daniel, D. G., Campbell, H., and Turnbull, A. C.: Puerperal thromboembolism and suppression of lactation, Lancet, 2:287, 1967. 34. Hilton, B. P., and Cumings, J. N.: An assessment of platelet aggregation induced by 5-hydroxytryptamine, J. Clin. Path. 24:250, 1971. 35. Cotton, R. C., Bloor, K., and Archibald, G.: The effect of Pyridinolcarbamate on the platelet response to ADP in patients with intermittent claudication. Atherosclerosis II, Edit. Shimamoto, T., Numano, F., and Addison, G. M.; Publ. Excerpta Med., 1973. 36. Loisy, C., Arnaud, J. L., and Amelot, A.: Contribution to the study of histamine metabolism in migranous subjects, Res. Clin. Stud. Head., 3:252, 1972. 37. von Kaulla, E., Droegemueller, W., Aoki, N., and von Kaulla, K. N.: Antithrombin III depression and thrombin generation acceleration in women taking oral contraceptives, Am. J. Obst. Gyn., 109:868, 1971. 38. Fisch, I. R, Freedman, S. H., and Pellegrin, F. A.: Effect of oral contraceptives of the thromboelastogram, Clin. Pharm. Therap., 14:238, 1973. 39. Hockaday, J. M., and Whitty, C. W. M.: Factors determining the electroencephalogram in migraine: a study of 560 patients, according to clinical type of migraine, Brain, 92:769, 1969. 40. Slatter, K. H.: Some clinical and EEG findings in patients with migraine, Brain, 91:85, 1968. 41. Skinhøj, E.: Haemodynamic studies within the brain during migraine, Arch. Neurol., 29:95, 1973. 42. Marcus, J. A.: Platelet function. Part I-III, N.E.J.M., 280:1213, 1278, 1330, 1969. 43. Packham, M. A., and Mustard, J. F.: Platelet reactions, Sem. Haemat., 8:30, 1971. 44. Sicuteri, F.: Vasoneuroactive substances and their implication in vascular pain, Res. Clin. Stud. Head., 1:6, 1967. 45. Anthony, J., Hinterberger, H., and Lance, J. W.: The possible relationship of serotonin to the migraine syndrome, Res. Clin. Stud. Head., 2:29, 1969. 46. Irey, N. S., Manion, W. C., and Taylor, H. B.: Vascular lesions in women taking oral contraceptives, Arch. Path., 89:1, 1970. 47. Cutts, J. H.: Vascular lesions resembling polyarteritis nodosa in rats undergoing stimulation with oestrogen, Brit. J. Exp. Path., 47:401, 1967. 48. Mustard, J. F., Jørgenson, L., and Pack-ham, M. A.: Blood flow and platelet interaction with surfaces. Thromb. Diath. Haemorh. N, 57: 151, 1972. 49. Hockaday, J. M. Williamson, D. H., and Whitty, C. W. M.: Blood-glucose levels and fatty acid metabolism in migraine related to fasting, Lancet, 1:1153, 1971. 50. Jørgenson, L., Hovig, T., Rowsell, H. C., and Mustard, J. E.: Adenosine diphosphate-induced platelet aggregation and vascular injury in swine and rabbits, Am. J. Path., 61:161, 1970. 51. Zervas, N. T., Kuwayama, A., Rosoff, C. B., and Salzman, E. W.: Cerebral arterial spasm. Modification by inhibition of platelet function, Arch. Neurol., 28:400, 1973. 52. Karpatkin, S.: Heterogenity of human platelets. II. Functional evidence of young and old platelets, J. Clin. Invest., 48:1083, 1969. ACKNOWLEDGEMENT The following tests were performed in the Coagulation Laboratory of the Department of Medicine through the kindness of Kurt von Kaulla, M.D.: thrombin generation, antithrombin III activity, euglobulin lysis time, spontaneous platelet aggregation in platelet-rich plasma, thromboelastograms. Zdenka Kalendovsky, M.D., is the recipient of a Neurology Traineeship as part of Veterans Administration Training Program TR-176. The screen filtration pressure apparatus was purchased with a grant from the Japan Arteriosclerosis Research Foundation. Reprint requests to: Zdenka Kalendovsky, M.D. Department of Neurology University of Colorado Medical Center 4200 East 9th Avenue Denver, Colorado 80220