Celebrating
60 Years of
Caring
NHF Nursing Luncheon
November 14, 2008
Jim Munn, RN, MS
Hemophilia: Early Observations
- Second Century
For it was taught: If she circumcised her
first child and he died [as a result of
bleeding from the operation] and a second
one died [similarly], she must not
circumcise her third child.
R. Judah, the Patriarch, redactor of the Mishnah
Rosner F. Medicine in the Bible and the Talmud, revised ed, New York: Yeshiva University Press, Ktav
Publishing House, 1995.
Early Observations
Tenth Century Islamic Surgeon Abul Qasim
Al-Zahravi (Albucasis) 936-1013 CE
– Considered greatest surgeon of Middle Ages
– Referred to a condition interpreted by scholars
as hemophilia in his encyclopedic work on
medicine and surgery, al-Tasrif
Al-Tasrif Uman ‘Ajiza An Al-Taalif.
Early Observations
Twelfth Century Physician and Talmudist Maimonides states in the
Mishneh Torah1
“If a woman had her first son
circumcised and he died as a
result of the circumcision,
which enfeebled his strength,
and she similarly had her
second [son] circumcised and
he died as a result of the
circumcision - whether [the
latter child] was from her first
husband or her second
husband - the third son may
not be circumcised at the
proper time [on the eighth day
of life]…”2
1. Rosner F. “Moses Maimonides.” Ann Intern Med. 1965;372:1135-1204.
2. Mishneh Torah, Hilkhot Milah. 1:18.
Early Observations
1803: John Conrad Otto
 Provided first accurate account
of hemophilia in the modern
medical literature
 His investigation of “bleeders”
was published in a New York
journal under the title, “An
Account of an Hemorrhagic
Disposition Existing in Certain
Families”
 Traced to woman who settled
in Plymouth, New Hampshire
in 1720
Otto JC. The Medical Repository. 1803;Vol VI (No 1):1-4.
Early Observations
1820: Nasse of Bonn
– German physician 1778-1851
– Formulated observations on inheritance of
hemophilia
– “Nasse’s Law”

Transmitted by unaffected females to their sons
Nasse CF. Arch Med Erfahr. 1(1820):385.
Early Observations


1828: The word “hemophilia” first appears in a
description of inherited bleeding disorders by
Physician Frederick Hopff at the University of
Zurich
1840: First recorded case of hemophilia treatment
by transfusion written by Samuel Lane in The
Lancet

1
1893: First documentation of abnormal
prolongation of coagulation in capillary tube in
hemophilics2
1. Farr AD. J Royal Soc Med. April 1981;74(4):301-305.
2. Wright AE. Br Med J. 1893;2:223-225.
Early Observations:
Other Highlights of the Early 1900s





1911: Publication of “monumental review of pedigrees of
families with bleeding disorders”1
1920-1930: Hemophilia treatments published; plasma for
transfusions introduced
1926: Erik vonWillebrand describes bleeding disorder
affecting both sexes
1937: IV administration of redissolved plasma precipitate
shown to shorten blood clotting time2
1937: First permanent blood bank established in US
1. Ingram GIC. J Clin Pathol. 1976;6:3.
2. Brinkhous KM. A Short History of Hemophilia. Handbook of Hemophilia.
New York: American Elsevier, 1975.
1940s
Early to Mid-1940s: Medical progress accompanies war
– Charles Drew sets standard for collecting, storing
and transporting plasma under “battlefield
conditions”
– Edwin Cohn, Harvard biochemist, first to use
fractionation process to produce albumin in 19441
– Albumin usefulness spurs research in blood
component therapy by “clotters”
– 1946-1947: Hemophilia defect in plasma
component2
1. Latham A Jr. Vox Sang. 1986;51(3):249-52.
2. Brinkhous KM. Proc Soc Exper Biol and Med. Oct. 1947;66:117-120.
1940s
1948: A golden decade
for coagulation
research begins
 Hemophilia
Foundation
established 6/15/48
 Hemophilic dog colony
established: Chapel
Hill, North Carolina
©UNC Center for Thrombosis and Hemostasis
Smith N. A History of the National Hemophilia Foundation.
New York: National Hemophilia Foundation, 1984.
1950s


First
recommendation
for home infusion
1959: First
hemophilia
treatment center
in Rochester, NY
Photos of Mary Gooley (above) courtesy of the
Mary M. Gooley Hemophilia Center, Rochester, NY
Smith N. A History of the National Hemophilia Foundation. New York:
National Hemophilia Foundation, 1984.
1950s
Biggs R, et al. Br Med J. Dec. 27, 1952;1378. With permission from BMJ Publishing Group.
1950s
1952: Evolution of the definition of hemophilia:
– A blood clotting disorder affecting males with two
possible major protein deficiencies:
•
•
FVIII - Hemophilia A
FIX - Hemophilia B
– Thromboplastin generation test for measuring
FVIII developed
– Coagulation cascade discovered
Langdell RD, et al. J Lab Clin Med. 1953;41:637-647.
1950s
1958: First use of prophylaxis in Hemophilia A
conducted in Sweden by Prof. Inga Marie
Nilsson
1960s



1960s: NIH grants create research climate
1961: Hyland Laboratories begins work on FVIII
concentrate
1966: Peanut flour touted as treatment for hemophilia –
Nature 1
1. Nature. February 13, 1969. Vol. 185, No. 4711, pp. 469-470.
1960s
1965:
Discovery of
Cryoprecipitate
Judith Graham Pool, MD
File photo courtesy of HANDI, NHF.
Pool JG, Shannon AE. N Engl J Med. 1965:273:1443-1447.
1960s


1966: Hyland
announces commercial
availability of FVIII
concentrates
1969: FIX concentrate
licensed1
1. Hoag MS, et al. N Eng J Med.1969;280(11):581-6.
1960s



Continuous infusion
Predictable and sustained level over time
Cost savings due to decreased
– Laboratory evaluations
– Clearance over time
Ideal replacement for surgical interventions and
specific bleeding episodes in hemophilia
McMillan CW, et al. Br J Haematol. 1970;18:659-667.
Hathaway WE, et al. Am J Hematol.1984;17:85-88.
Shulman NR, et al, Ann Intern Med. 1967;67:856.
1960s
1969:
First hemophilia camp established
1970s





1.
2.
3.
1970s: Home infusion therapy: a common
treatment practice
1971: von Willebrand’s factor identified¹
1974: First successful immune tolerance²
1975: Federally funded comprehensive
hemophilia treatment centers initiated
1977: Mannucci discovers DDAVP increases FVIII
and vWF levels3
Zimmerman, TS, et al. J Clin Invest.1971;50:244-254.
Brackmann HH, Lancet 1977; 2 (8044): 933.
Mannucci PM. Lancet. 1977;1:869-872.
Regional Hemophilia
Treatment Center Network
1970s
Revisiting use of Prophylaxis
UK study – 9 boys with Hem A <1%
- Randomized, blinded, crossover study
- Had target joints present
- Received 25% correction with FVIII or placebo once a
week, followed by week of rest
- Showed 15% reduction in bleeding episodes in 100 day
period (from 13.6 episodes to 11.6)
- 66% decrease in bleeds in first three days of the week
Aronstam. 1976. Brit J Haematol. 33:81.
.
1970s
Transmission of blood-borne diseases:
– Hepatitis B: HBV
– Hepatitis non-A, non-B: Later called “C”
– HIV
Mannucci PM, et al. J Clin Pathol. 1975;28(8):620-624.
Schramm W, et al. Blut. 1989;59(4):390-392.
Hepatitis B Virus: HBV







Lipid-enveloped DNA virus
Replicates within liver cells
Transmitted by exchange of
bodily fluids
90% recover with immunity;
10% develop chronic HBV of
which
20-30% progress to
cirrhosis
Virion sensitive to heat and
solvent/detergent
1981: Hep B vaccine plasma
derived
1987: Hep B vaccine
recombinant licensed
Electron micrograph of Hepatitis B
Virions courtesy of the CDC
The Price of Independence
Non-A, non-B (Hepatitis C) recognized as
transmissible via plasma-derived products
– 1986: Commercial screening for non-A, non-B
hepatitis surrogate markers
– 1989: Hepatitis C isolated
– 1990: Hepatitis C Ab testing of donated blood
begins
Hepatitis C Virus: HCV

Lipid-enveloped RNA virus

Replicates within infected liver cells

Transmitted by the exchange of bodily fluids

85% or more with acute HCV infection progress
to chronic hepatitis*

Virion sensitive to heat and solvent/detergent

No vaccine available
* Seeff LB. Am J Med. Dec. 1999;107[6B]:10S-15S.
1980s
MMWR July 16, 1982/31(27):365-367.
The Price of Independence

1983: Suspicion that HIV threatened the worldwide blood supply
April 1, 1983: Hemofil-T, first heat-treated FVIII concentrate in the U.S.
1984: Montagnier1 and Gallo2 discover HTLV-3 (HIV)
1984: Efficacy of heat treatment for viral inactivation demonstrated
1984: Recall of blood products initiated
1985: ELISA test used to detect HIV antibodies among blood donors

1985: Safety net:





1.
2.
3.
Donor deferral
Viral inactivation methods
HIV antibody testing
1. Barre-Sinoussi F, et al. Science 1983; 220(4599):868-71.
2. Gallo RC, et al. Science 1984; 4;224(4648):500-3.
The Heroes We Care For
Photo courtesy of Mary Lou Cygan, R.N., P.N.P.
1980s
1990s

1991 – Karolinska University – Stockholm, Sweden
Dr. Petrini and colleagues describe prevention of
joint disease in boys with hemophilia under age
two.
Lusher, J. 2008. HemAware. 13: 8.
1990s
HTC (%)
Non-HTC (%)
P
Mild
21.8
52.8
<.001
Moderate
24.2
26.7
Severe
54.0
20.5
6.0
2.3
<.001
Characteristics
Severity
Inhibitors
Liver disease
2.3
0.7
.002
HIV infection
31.1
17.1
<.001
AIDS
8.2
5.9
.02
Soucie JM, et al. Blood. 2000;96(2):437-442.
1990s
Mortality decreased 40% in patients using a
comprehensive hemophilia treatment center
(HTC)
“The finding that HTCs have a significant effect on
reducing mortality in patients with hemophilia supports
the effectiveness of such centers in providing specialized
preventative care.”
Soucie JM, et al. Blood. 2000;96(2):437-442.
1990s
Prophylaxis recommendation

Primary
– Early institution ~ 1-2 years with the aim of maintaining
trough > 1%
– Longitudinal assessment of joint status essential

Secondary
– Appropriate for intervention to prevent joint and other
disease associated morbidities
MASAC Recommendation #35. March 11, 1994.
2000s




Gene therapy trials begun
Joint Outcome Study published1
National Pain Survey
Willetabs and Wilbrintin advertised as
treatment for vWD
Manco-Johnson, et al. NEJM. 2007. Vol. 357:(6) 535-544.
Hemophilia A: Evolution of Therapy
Year
Therapy
1950
Plasma (1-FVIII U/ml)
1966
Cryoprecipitate (5-FVIII U/ml)
1975
Lyophilized concentrates (30-FVIII U/ml)
1983
Heat treatment of lyophilized concentrates for viral attenuation
1985
Introduction of a solvent detergent for viral inactivation
1988
Monoclonal antibody-purified FVIII concentrates with heat or
solvent detergent treatment
1992
Recombinant DNA products: 1st generation
2000s
2nd & 3rd generation recombinant products
Hemophilia B: Evolution of Therapy
Year
Therapy
1950
Plasma (1-FIX U/ml)
1975
Lyophilized prothrombin complex concentrates or PCC (30-FIX
U/ml)
Heat treatment of lyophilized concentrates for viral attenuation
Development of a solvent detergent for viral inactivation
1985
1992
Chromatographic/monoclonal antibody-purified FIX concentrate
with ultrafiltration and thiocyanate treatment
1997
Recombinant DNA product
The Future







Longer acting concentrates
Recombinant therapy for vWD
Alternate route therapies
Gene transplantation
Elimination of transfusion-associated infections
Understand and overcome inhibitor development
Quality of life issues
– Elimination of joint morbidity
– Optimizing the individual’s social and academic
performance
The Future…
…the promise of achieving your potential