DISCUSSION PAPER: HISTORICAL COMMENTS ON HEMOPHILIA AND CARRIER DETECTION

Paul Didisheim

Section of Laboratory Hematology Department of Laboratory Medicine

Mayo Clinic and Mayo Medical School Rochester, Minnesota 55901

You have just been hearing about the latest developments regarding hemo- philia and ways of detecting the carrier state. It is occasionally useful to recall what some of the earliest observations in a field have been. What you will hear from me is nothing new. In fact it is very, very old, and may be of interest for that reason.

One of the earliest known mentions of what may have been hemophilia and its inheritance was in the Babylonian Talmud, probably written in the third century A.D.: “It has been reported of four sisters of Sephoris: the first one circumcised her son, and he died; the second, and he died; the third, and he died; then the fourth came before Rabban ben Gamaliel, who said to her: abstain from circumcision . . . for there are families whose blood is loose, while in others it coagulates.” *

Several explanations come to mind. One is that the rabbi who performed the three fatal circumcisions was a very bad surgeon. The usual explanation given, however, is that the three sisters whose sons died were carriers of hemo- philia and that the rabbi’s advice to the fourth sister was wise, since she may therefore also have been a carrier. It is unfortunate that the third sister didn’t consult the rabbi, who might have given her the same good advice he gave the fourth sister.

McKusick has pointed out that in 1791 the Salem, Mass., Gazette contained an obituary of Isaac Zoll, age 19, whose death was occasioned by a slight cut in his foot from which bleeding could not be stopped until he expired.? The account continues, “five brothers to the above person have bled to death” from minor cuts or bruises. “The father of the above persons has had two wives, and by each, several children; those who died in this singular manner were all of the first wife.” This may have been the first report of probable hemophilia in the United States.

In 1803 Dr. Otto of Philadelphia reported in the Medical Repository on a family from Plymouth, N.H., that was affiicted with a tendency to severe bleed- ing following the slightest scratch.3 He wrote, “it is a surprising circumstance that the males are subject to this strange affection . . . although the females are exempt, they are still capable of transmitting it to their male children.”

In 1813 Dr. John Hay of Reading, Mass. reported an “Account of a re- markable haemorrhagic dispostion existing in many individuals in the same family.” 4 McKusick has reconstructed this pedigree from Hay’s account, extending over 14 generations. The first known bleeder was Oliver Appleton of Ipswich, born in 1677. Dr. Hay recognized the characteristic sex-linked inheritance. In 1962 one of the cochairmen of this conference, Dr. Rapaport, reported results of the factor VIII assay in a descendant, a daughter of a male

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Didisheim : Discussion Paper: Carrier Detection 139

bleeder in this pedigree. She was found to have a subnormal factor VIII level. This probably identifies the pedigree as being one of classic hemophilia.

Without question the most famous family affected with a bleeding disorder is that of Queen Victoria.5 In 1853 she gave birth to the eighth of her nine children, Leopold, who was soon noted to have an unusual tendency to bleed even from trivial injuries. It became evident in ensuing generations that two of Queen Victoria's daughters were carriers of the gene. In all, there have been at least ten male bleeders. Nicholas and Alexandra, whose lives have recently been repopularized in a book" and on the screen, were the parents of the ill-fated Czarevitch Alexei, who along with his family was shot in 1918 during the Bolshevik Revolution. Alexei's sister Anastasia had a 50% chance of being a carrier. If she survived the revolution, as some believe and as Ingrid Bergman has portrayed on the screen, the hemophilic trait in this royal family may have been transmitted to the present day. Whether this family was afflicted by factor VIII or IX deficiency is either unknown or a closely guarded family secret.

This century has witnessed numerous efforts to detect the hemophilic carrier state in the laboratory. At least as far back as 1906 occasional reports have mentioned that obligatory carriers may show an abnormality of coagulation either in whole blood or in plasma. Many in this room, including Dr. Ratnoff. the chairman of this session, have contributed significantly to this area. In 1958 we reported reduced factor VIII clotting activity and thromboplastin generation in some obligatory carriers of classic hemophilia. We obtained similar results with respect to factor IX clotting activity and the T G T in carriers of factor IX deficiency.;

In the past decade, studies by Nilsson, Rapaport, and van Creveld and their colleagues, ourselves, and others have shown that 75 to 100% of obligatory carriers of factor VIII or IX deficiency are detectable by specific factor assay, without benefit of immunoassay.s-ll Some of the obligatory carriers of hemo- philia may in fact have had von Willebrand's disease, but many of their affected male relatives had severe factor VIII clotting defects while the women were mildly affected. In those families at least, this explanation seems unlikely. Furthermore, this explanation does not account for the results in obligatory carriers of factor IX deficiency, wherein 79 and 87% of the carriers were detectable by factor IX clotting assay in two series.

Therefore, while the new immunoassay techniques may increase the sensi- tivity and specificity of carrier detection and are certainly contributing to our understanding of the nature of these disorders, we weren't doing all that badly before.

REFERENCES

1. A Talmudic reference to hemophilia and its genetic transmission. Babylonian Talmud, tractate Yebamot. fol. 64. p. 2. Translated into English in Israel J. Med. Sci. 1965. 1: 593.

2. MCKUSICK, V. A. 1962. The earliest record of hemophilia in America? Blood

3. OTTO, J. C. 1803. An account of an haemorrhagic disposition existing in cer- tain families. Med. Repository 6: 1; Major, R. H., Ed. 1945. Classic De- scriptions of Disease. 3rd edit. : 522-524. Charles C Thomas. Springfield, Ill.

4. HAY, J . 1813. Account of a remarkable haemorrhagic disposition, existing in

19: 243-244.

140 Annals New York Academy of Sciences

many individuals in the same family. New Eng. J. Med. 2: 221; McKusick, V. A. 1962. Hemophilia in early New England. A follow-up of four kin- dreds in which hemophilia occurred in the pre-revolutionary period. J. Hist. Med. 17: 342-365; McKusick, V. A. & Rapaport, S. I. 1%2. History of clas- sical hemophilia in a New England family. Arch. Int. Med. 1 1 0 144-149.

5 . MCKUSICK, V. A. 1965. The royal hemophilia. Sci. Amer. 213(2): 88-95. 6. MASSIE, R. K. 1967. Nicholas and Alexandra. Atheneum. New York, N. Y. 7. DIDISHEIM, P., J. H. FERGUSON & J. H. LEWIS. 1958. Hemostatic data in rela-

tives of hemophiliacs A and B. Evidence for modifying the classical sex- linked recessive hypothesis. Arch. Int. Med. 101: 347-354.

8. RAPAPORT, S. I., M. J. PATCH & F. J. MOORE. 1960. Antihemophilic globulin levels in carriers of hemophilia A. J. Clin. Invest. 3 9 1619-1625.

9. NILSON, I. M., M. BLOMBACK, 0. RAMCREN & I. V. FRANCKEN. 1962. Haemo- philia in Sweden. 11. Carriers of haemophilia A and B. Acta Med. Scand. 171: 223-235.

10. DIDISHEIM, P. & R. L. E. VANDERVOORT. 1962. Detection of carriers for factor IX (PTC) deficiency. Blood 2 0 150-155.

11. MULDER, E., I. A. MOCHTAR, S. VAN CREVELD & E. B. LOPES CARDOZO. 1965. Factor VIII activity in carriers of haemophilia A. Brit. J. Haemat. 11: 206- 209.

DISCUSSION

DR. RATNOFF: I have heard that an alleged descendant of the royal family has classic hemophilia. This is rumor-mongering, because I have not seen this patient.