Twelve Diseases that Changed Our World. Irwin W. Sherman

a wound until the circulatory system collapses—the afflicted person hemorrhages to death. Blood clotting is a complex affair involving a cascade of protein-protein interactions that converts a soluble protein of blood plasma, fibrinogen, into insoluble protein fibers of fibrin. The clotting cascade is like the Mother Goose rhyme “This is the house that Jack built”: This is the cat, that killed the rat, that ate the malt, that lay in the house that Jack built. In the clotting cascade: This is the break in the skin, so factor VIII can begin, converting prothrombin to thrombin; when thrombin converts fibrinogen to fibrin, the cross-linked result produces clottin'.

      Eighty-five percent of all persons with hemophilia lack factor VIII, one of the clotting factors; the remainder lack factor V. In the absence of such factors, the individual may suffer internal hemorrhages after a minor bump or may die at an early age due to a bleeding crisis. It is possible to diagnose hemophilia as early as the eighth week of pregnancy by DNA hybridization techniques, but in the time of Queen Victoria no such test was available. In recent years, hemophiliacs could be treated with intravenous transfusions of a concentrated form of factor VIII that had been prepared from normal plasma. This form of treatment dramatically lengthened the life expectancy of hemophiliacs from about 20 years to more than 60. However, this therapy was unavailable before 1960, and even when it did become possible to correct hemophilia with transfusion of factor VIII, the dangers of the recipient becoming infected with human immunodeficiency virus and hepatitis virus from such preparations were great indeed. This complication of virus-contaminated preparations has been avoided since 1986, when the gene for factor VIII was cloned, making it possible to synthesize large quantities of “pure” factor VIII in virus-free tissue culture cells.

      What is the cause of defective factor VIII? It can be the result of mutations (a change in a single nucleic acid base in the DNA) that produce a shortened version of factor VIII, leading to severe hemophilia, or there can be a complete absence of factor VIII, also leading to severe hemophilia. However, if the mutation results in the insertion of a “wrong” amino acid in factor VIII, the resulting hemophilia is mild.

      “Catching” hemophilia

      How did Queen Victoria transmit hemophilia to some of her children and grandchildren? Indeed, how did she herself come to be a carrier? Our gender is determined at the moment of fertilization. Each of our somatic (body) cells contains within its nucleus 44 autosomes and one pair of sex chromosomes. During the formation of sperm and eggs, two kinds of sperm are possible (one with an X and one with a Y chromosome) but only one kind of egg occurs (with an X chromosome). Determination of the gender of an offspring depends on the sex chromosome of the fertilizing sperm. If the fertilizing sperm carries an X chromosome, the offspring will be female, and if the fertilizing sperm carries a Y chromosome, the offspring will be male. Genes that are carried on either the X or Y chromosome are called sex-linked genes. The defective gene for hemophilia is carried only on the X chromosome. Since males have only one X chromosome, they have symptomatic hemophilia if they carry the defective form of the gene for factor VIII. However, females, having two X chromosomes, would have to have a double dose of the defective gene to show signs of hemophilia. This is unlikely since the chance of a person having both a hemophiliac father and a carrier mother is quite remote, and females who are hemophiliac die before maturity because the onset of menstruation is fatal.

      Hemophiliac fathers pass on the recessive gene to all their daughters but not to any of their sons, because the son receives a Y chromosome, not an X chromosome, from the father. Carrier mothers, i.e., those who carry one normal and one defective gene, have a 50% chance of passing the defective gene to their offspring; affected sons are hemophiliacs, and affected daughters are carriers.

      Since there is no record of hemophilia in Queen Victoria's ancestors, it is presumed that either she developed a mutation in the gene for factor VIII in her embryonic cells or a mutation occurred in the X chromosome of one of her parents' germ cells. An alternative possibility, although one for which no real evidence exists, is that she was the illegitimate daughter of a hemophiliac father. Queen Victoria had nine children by her husband, Albert, Prince of Saxe-Coburg and Gotha. Princess Alice (1843 to 1878), Victoria's third child and second daughter, married Prince Louis of Hesse at an early age and had seven children, one of whom, Frederick, was a hemophiliac who died at the age of 3 after falling out of a window. Princess Alice, along with her youngest daughter, May, died of diphtheria in 1878. Her sixth child, Alix, was only 6 years old when her mother died. Alix was a favorite grandchild of Queen Victoria, who hoped that Alix would marry Albert Victor (Duke of Clarence and Avondale), the Queen's grandson and the eldest son of the Prince of Wales (later Edward VII). Alix, however, did not take to the unimpressive Albert Victor, who was rather deaf and somewhat retarded. Had such a union been consummated, Alix's carrier status for hemophilia could have introduced the disease into the British royal family. Instead, she introduced the defective gene into the House of Romanov, the royal family of Russia, and thus contributed to its downfall.

      Death of the House of Romanov

      Alix first met the Tsarevich Nicholas when she was 12 years of age; 5 years later, they met again and fell in love; they married in 1894, 1 week after the death of Nicholas' father, Tsar Alexander III. Although hemophilia had already been recognized in Victoria's descendants (her son Prince Leopold Duke of Albany died of hemophilia, as did her grandson Frederick of Hesse), the risk was largely unappreciated and/or the value of marrying into a powerful royal house (and a potential ally) took precedence over prudence. On her marriage to the 26-year-old Tsar Nicholas II, Alix took the name Alexandra Feodorovna. Their first four children, born between 1895 and 1901, were girls; this made Alexandra increasingly neurotic since the first duty of a Tsarina was to maintain the House of Romanov by producing a male heir. In 1904, they had a son, Alexis. Alexandra soon discovered that the Tsarevich Alexis was bleeding excessively from the umbilicus and that he had inherited hemophilia. The fragile health of her longed-for son caused her to become more and more withdrawn. She dwelt morbidly on the fact that she had transmitted the disease to her heir. Alexis' condition was kept secret from everyone except close family and their physicians because such a defect would have been regarded as a sign of divine displeasure since the Tsar was both head of the Church and leader of the Russian people. In the summer of 1907, Alexandra was introduced to a “holy man,” the monk Gregorii Rasputin (who was born in Siberia in about 1860 to 1865). Rasputin's appearance and demeanor were those of a disheveled vagrant; in addition, he was debauched, alcoholic, coarse, lecherous, and a rapist. He was, however, a charismatic man and a great hypnotist. He recognized and encouraged the Tsarina's fascination for the Russian spirit and her desire to be the soul-mother of its simple people. More importantly, he was able to soothe and calm the distressed and sometimes hysterical Alexis during bouts of hemophilia and hence help stop the bleeding. Increasingly the Tsar and Tsarina came to depend on him. Indeed, in 1907 Alexis recovered from a near-death experience when Rasputin simply stood at the foot of the bed and prayed; he never once touched the child. Again, in 1912, when Alexis was 8 years old, he was bruised while playing in a bathtub and hemorrhaging began. Alexandra once again contacted Rasputin, who responded by telegram that all would be well, and almost miraculously Alexis began to recover. As a result, Rasputin enjoyed increasing personal and political influence with the Tsar and Tsarina, influence which he did not hesitate to take advantage of.

      The assassination of Archduke Ferdinand and his wife Sophie in Sarajevo on 28 June 1914 by a Serbian extremist signaled the beginning of the Russian Revolution and the end of the House of Romanov. Three days before Ferdinand, heir to the throne of the Austro-Hungarian Empire, was shot dead, Alexis had slipped on a ladder on his father's yacht, sustaining an injury that resulted in excessive bleeding around the ankles. To complicate matters further, Rasputin had been stabbed in his hometown in Siberia and was unable to minister to the seriously ill Tsarevich. Regarding the international situation, Rasputin wrote from his sick bed: “Let Papa [Nicholas] not plan for war, for with war will come the end of Russia and yourselves and you will lose to the last man.” For once, Nicholas ignored Rasputin's advice and mobilized the army against Austria. As a result of the Triple Alliance between Germany, Austria, and Italy, this action meant that Tsar Nicholas of Russia was at war with his cousin-in-law Wilhelm II of Germany, who in turn was at war with his cousin King George V of Great Britain. In the first year, Russia lost