Hemophilia historical perspective

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]


Hemophilia is considered a very old disease with its history dating back to the 2nd century AD. The first modern descriptions of the condition appeared during the 19th century. Extensive work has been done over the centuries regarding the classification, inheritance pattern, and treatment of hemophilia.

Historical Perspective


  • References to a condition associated with bleeding and suggestive of hemophilia date back to the 2nd century AD.[1][2]
  • Ancient religious script compilations, such as The Babylonian Tarmud, have also mentioned the condition along with relative fatal bleeding episode prevention.[2][3]
  • Abu Qasim Khalaf Ibn Abbas Al Zahrawi, a pioneer of modern surgery, known in the West as Albucasis or Zahravius, described suspected hemophilia cases in the 10th century.
  • G. W. Consbruch of Bielefeld, Germany, described a bleeding disease very similar to hemophilia in 1793.
  • Dr John Conrad Otto, an American physician, takes the credit for the first modern description of hemophilia in 1803. He described a bleeding disorder, transmitted via unaffected females and affecting only males. His work was published under the title “An account of an hemorrhagic disposition existing in certain families”.[4]
  • In 1813, John F. Hay published his first analysis of a hemophilia family tree in the New England Journal of Medicine.[3]
  • Christian Friedrich Nasse, a German physician and psychiatrist, described the genetics of hemophilia in 1820 and his work resulted in Nasse's law, which states that hemophilia is transmitted entirely by unaffected females to their sons.[5]
  • A German physician, Johann Lukas Schönlein and his student Friedrich Hopff, documented the word "hemophilia" for the first time in 1828 and the condition was described in his dissertation with the title "About hemophilia or the hereditary predisposition to fatal bleeding".[6]
  • Nasse's law prompted further scientific debate leading to publications by J. Grandidier in 1855, John Wickham Legg in 1872, and Hermann Immermann in 1879.[3]
  • The analysis of a hemophilia family tree by John F. Hay was followed by the analyses from Sir William Osler in 1885, Kathleen P. Pratt in 1908, F. Koller and his group in 1954, and Victor A. Mckusick and Samuel I. Rapaport in 1962.
  • William Bulloch and Paul Gordon Fildes published a detailed description of the early history of hemophilia in 1912 under the title "Treasury of human inheritance".[7]

Discovery of the Antihemophilic Globulin

  • A. E. Wright was the first who documented the prolonged clotting time of hemophilic blood in a capillary tube in 1893.[8]
  • In 1908, P. Morawitz and J. Lossen proposed a deficiency in thrombokinase associated with hemophilia and disproved the association with calcium deficiency.[8]
  • In 1911, T. Addis investigated several blood and tissue factors and concluded that the hemophilic blood has defective prothrombin.[9]
  • In 1931, P. Govaerts and A. Gatia proposed that the platelets from hemophilic blood behaved normally when shifted to normal plasma. This finding hinted towards a deficiency in the plasma.[3]
  • In 1934, S. Van Creveld demonstrated that a “dispersed protein” fraction obtained from the serum decreased the clotting time of hemophilic blood.[10]
  • In 1936, A.J. Patek and F.H.L. Taylor proposed in their publication in Science that in normal blood and in citrated normal plasma rendered free from platelets by Berkefeld filtration, a substance was identified which, in small quantities, reduced the clotting time of hemophilic blood. Between 1936 and 1946, this research group published multiple papers supporting their original hypothesis[11][12]
  • A.J. Quick, M. Stanley-Brown, F.W. Bancroft solved the question of whether prothrombin or one of its derivatives is the deficient factor in hemophilia. They concluded that the hemophilic blood has a normal prothrombin content.[13]
  • In 1939, Brinkhous et al. confirmed A.J. Quick's findings and showed that the hemophilic blood has a delayed prothrombin conversion rate.[14]
  • In 1947, A.j. Quick and K.M. Brinkhous independently demonstrated that the antihemophilic globulin and platelets react together in a fashion to generate thromboplastin. They also proposed that a deficiency in antihemophilic globulin caused defective coagulation due to defects in the generation of thromboplastin.[15][14]

Landmark Events in the Development of Treatment Strategies

Transfusion Medicine

Evolution of the Treatment Strategies

Year Therapy
  • "Antihemophilic globulin" introduced as a term[27][28]

Clotting Factor Concentrates and its Evolution to Modern Treatment

Year Therapy
  • The first recombinant factor VIII product is introduced and registered
2004 - current
  • Developmental breakthroughs in the recombinant factor VIII products

Famous Cases

Hemophilia has been called "the disease of the kings" or "the royal disease" as several members of the European royal family have been affected by it.[31] The following are a few famous cases of hemophilia:

  • The Queen of England, Queen Victoria (1837–1901), was a carrier of hemophilia and she passed it onto her son, Leopold, who died of a brain hemorrhage when he was 31.[31]
  • The disease spread to other royal families in Germany, Russia and Spain through Queen Victoria’s two daughters.
  • The best known case of "the royal disease" was Tsarevich Alexei, son of the Russian Czar Nicholas II.


  1. Brinkhous, K. M. (1975). Handbook of hemophilia. Amsterdam New York: Excerpta Medica Sole distributors for the U.S.A. and Canada, American Elsevier Pub. Co. ISBN 9789021920962.
  2. 2.0 2.1 Rosendaal FR, Smit C, Briët E (February 1991). "Hemophilia treatment in historical perspective: a review of medical and social developments". Ann. Hematol. 62 (1): 5–15. PMID 1903310.
  3. 3.0 3.1 3.2 3.3 Ingram, G. I. C. (1997). "The history of haemophilia*,†". Haemophilia. 3 (S1): 5–15. doi:10.1111/j.1365-2516.1997.tb00168.x. ISSN 1351-8216.
  4. Otto JC (July 1996). "An account of an hemorrhagic disposition existing in certain families". Clin. Orthop. Relat. Res. (328): 4–6. PMID 8653976.
  5. Brinkhous, K. M. (1975). Handbook of hemophilia. Amsterdam New York: Excerpta Medica Sole distributors for the U.S.A. and Canada, American Elsevier Pub. Co. ISBN 9789021920962.
  6. Krieger, Marie (1920). Über die Atrophie der Menschlichen Organe bei Inanition. Berlin, Heidelberg: Springer Berlin Heidelberg Imprint Springer. ISBN 3662229374.
  7. Francis, Sir, Bulloch, William (1909). Treasury of human inheritance. London: Cambridge University Press.
  8. 8.0 8.1 Wright AE (July 1893). "On a Method of Determining the Condition of Blood Coagulability for Clinical and Experimental Purposes, and on the Effect of the Administration of Calcium Salts in Haemophilia and Actual or Threatened Haemorrhage: [Preliminary Communication]". Br Med J. 2 (1700): 223–5. PMC 2422001. PMID 20754381.
  9. 9.0 9.1 Addis, T. (1911). "The pathogenesis of hereditary hæmophilia". The Journal of Pathology and Bacteriology. 15 (4): 427–452. doi:10.1002/path.1700150402. ISSN 0368-3494.
  10. 10.0 10.1 10.2 Creveld, S.; Jordan, F. L. J.; Punt, K. (2009). "Deficiency ot Anti-Hemophilic Factor in a Woman, Combined with a Disturbance in Vascular Function.1". Acta Medica Scandinavica. 151 (5): 381–389. doi:10.1111/j.0954-6820.1955.tb10306.x. ISSN 0001-6101.
  11. "Commentary on and reprint of Patek AJ Jr, Taylor FHL, Hemophilia. II. Some properties of substances obtained from human plasma effective in accelerating coagulation of hemophiliac blood, in Journal of Clinical Investigation (1937) 16:113–124". 2000: 573–585. doi:10.1016/B978-012448510-5.50144-8.
  12. Hynes HE, Owen CA, Bowie EJ, Thompson JH (March 1969). "Development of the present concept of hemophilia". Mayo Clin. Proc. 44 (3): 193–206. PMID 4887314.
  13. Pisciotta AV (August 1980). "Concepts of haemostasis and thrombosis: A study of the coagulation defect in hemophilia and in jaundice (Quick, Stanley-Brown and Bancroft 1935). Armand J. Quick (1894-1978)--a short biography". Thromb. Haemost. 44 (1): 1–5. PMID 6999657.
  14. 14.0 14.1 Brinkhous, K. M. (1947). "Clotting Defect in Hemophilia: Deficiency in a Plasma Factor Required for Platelet Utilization". Experimental Biology and Medicine. 66 (1): 117–120. doi:10.3181/00379727-66-16003. ISSN 1535-3702.
  15. QUICK AJ (September 1947). "Studies on the enigma of the hemostatic dysfunction of hemophilia". Am. J. Med. Sci. 214 (3): 272–80. PMID 20263163.
  16. 16.0 16.1 Lane, Samuel (1840). "HÆMORRHAGIC DIATHESIS". The Lancet. 35 (896): 185–188. doi:10.1016/S0140-6736(00)40031-0. ISSN 0140-6736.
  17. Bergmann, E. v. (2013). Die Schicksale der Transfusion im Letzten Decennium : Rede, Gehalten zur Feier des Stiftungstages der Militärärztlichen Bildungsanstalten am 2. August 1883. Berlin: Springer Berlin Heidelberg. ISBN 9783642619298.
  18. Ringer, Sydney (1882). "Regarding the Action of Hydrate of Soda, Hydrate of Ammonia, and Hydrate of Potash on the Ventricle of the Frog's Heart". The Journal of Physiology. 3 (3–4): 195–202. doi:10.1113/jphysiol.1882.sp000095. ISSN 0022-3751.
  19. Tan, SY; Graham, C (2013). "Karl Landsteiner (1868–1943): Originator of ABO blood classification". Singapore Medical Journal. 54 (5): 243–244. doi:10.11622/smedj.2013099. ISSN 0037-5675.
  20. "Commentary on and reprint of Landsteiner K, Ueber Agglutinationserscheinungen normalen menschlichen Blute [On the agglutination of normal human blood], in Wiener Klinische Wochenschrift (1901) 14:1132–1134". 2000: 769–775. doi:10.1016/B978-012448510-5.50165-5.
  21. Eckhardt, Christian (1988). Transfusionsmedizin : Grundlagen · Therapie · Methodik. Berlin, Heidelberg: Springer Berlin Heidelberg Imprint Springer. ISBN 9783662106020.
  22. Ottenberg, Reuben; Kaliski, David (2009). "Die Gefahren der Transfusionen und deren Verhütung". DMW - Deutsche Medizinische Wochenschrift. 39 (46): 2243–2247. doi:10.1055/s-0028-1128886. ISSN 0012-0472.
  23. 23.0 23.1 Addis, T. (1916). "The effect of intravenous injections of fresh human serum and of phosphated blood, on the coagulation time of the blood in hereditary hemophila". Experimental Biology and Medicine. 14 (1): 19–23. doi:10.3181/00379727-14-14. ISSN 1535-3702.
  24. 24.0 24.1 Bendien, W. M. (1937). "INVESTIGATIONS ON HEMOPHILIA". Archives of Pediatrics & Adolescent Medicine. 54 (4): 713. doi:10.1001/archpedi.1937.01980040017002. ISSN 1072-4710.
  25. Macfarlane, R.G.; Barnett, Burgess (1934). "THE HÆMOSTATIC POSSIBILITIES OF SNAKE-VENOM". The Lancet. 224 (5801): 985–987. doi:10.1016/S0140-6736(00)43846-8. ISSN 0140-6736.
  26. "Commentary on and reprint of Patek AJ Jr, Taylor FHL, Hemophilia. II. Some properties of substances obtained from human plasma effective in accelerating coagulation of hemophiliac blood, in Journal of Clinical Investigation (1937) 16:113–124". 2000: 573–585. doi:10.1016/B978-012448510-5.50144-8.
  27. Minot GR, Davidson CS, Lewis JH, Tagnon HJ, Taylor FH (September 1945). "THE COAGULATION DEFECT IN HEMOPHILIA: THE EFFECT, IN HEMOPHILIA, OF THE PARENTERAL ADMINISTRATION OF A FRACTION OF THE PLASMA GLOBULINS RICH IN FIBRINOGEN". J. Clin. Invest. 24 (5): 704–7. doi:10.1172/JCI101654. PMC 435506. PMID 16695264.
  28. Taylor FH, Davidson CS, Tagnon HJ, Adams MA, Macdonald AH, Minot GR (September 1945). "STUDIES IN BLOOD COAGULATION: THE COAGULATION PROPERTIES OF CERTAIN GLOBULIN FRACTIONS OF NORMAL HUMAN PLASMA IN VITRO". J. Clin. Invest. 24 (5): 698–703. doi:10.1172/JCI101653. PMC 435505. PMID 16695263.
  29. Nilsson, I. M.; Berntorp, E.; Löfqvist, T.; Pettersson, H. (1992). "Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B". Journal of Internal Medicine. 232 (1): 25–32. doi:10.1111/j.1365-2796.1992.tb00546.x. ISSN 0954-6820.
  30. Pool, Judith Graham; Shannon, Angela E. (1965). "Production of High-Potency Concentrates of Antihemophilic Globulin in a Closed-Bag System". New England Journal of Medicine. 273 (27): 1443–1447. doi:10.1056/NEJM196512302732701. ISSN 0028-4793.
  31. 31.0 31.1 Ingram, G I (1976). "The history of haemophilia". Journal of Clinical Pathology. 29 (6): 469–479. doi:10.1136/jcp.29.6.469. ISSN 0021-9746.