Celebrating Celebrating 60 Years of 60 Years of

CaringCaringNHF Nursing LuncheonNHF Nursing Luncheon

November 14, 2008November 14, 2008

Jim Munn, RN, MSJim Munn, RN, MS

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.

Hemophilia: Early Hemophilia: Early ObservationsObservations

- Second Century- Second Century

Early ObservationsEarly Observations

Tenth Century Islamic Surgeon Abul Qasim Tenth Century Islamic Surgeon Abul Qasim Al-Zahravi (Albucasis) 936-1013 CE Al-Zahravi (Albucasis) 936-1013 CE – Considered greatest surgeon of Middle AgesConsidered greatest surgeon of Middle Ages– Referred to a condition interpreted by scholars Referred to a condition interpreted by scholars

as hemophilia in his encyclopedic work on as hemophilia in his encyclopedic work on medicine and surgery, medicine and surgery, al-Tasrifal-Tasrif

Al-Tasrif Uman ‘Ajiza An Al-Taalif.

Early Early ObservationsObservations

““If a woman had her first son If a woman had her first son circumcised and he died as circumcised and he died as a result of the circumcision, a result of the circumcision, which enfeebled his which enfeebled his strength, and she similarly strength, and she similarly had her second [son] had her second [son] circumcised and he died as circumcised and he died as a result of the circumcision a result of the circumcision - whether [the latter child] - whether [the latter child] was from her first husband was from her first husband or her second husband - the or her second husband - the third son may not be third son may not be circumcised at the proper circumcised at the proper time [on the eighth day of time [on the eighth day of life]…”life]…”22

1. Rosner F. “Moses Maimonides.” Ann Intern Med. 1965;372:1135-1204.2. Mishneh Torah, Hilkhot Milah. 1:18.

Twelfth Century Physician and Talmudist Maimonides states in the Mishneh Torah1

Early ObservationsEarly Observations

1803: John Conrad Otto1803: John Conrad Otto Provided first accurate Provided first accurate

account of hemophilia in account of hemophilia in the modern medical the modern medical literature literature

His investigation of His investigation of “bleeders” was published in “bleeders” was published in a New York journal under a New York journal under the title, “An Account of an the title, “An Account of an Hemorrhagic Disposition Hemorrhagic Disposition Existing in Certain Families”Existing in Certain Families”

Traced to woman who Traced to woman who settled in Plymouth, New settled in Plymouth, New Hampshire in 1720Hampshire in 1720

Otto JC. The Medical Repository. 1803;Vol VI (No 1):1-4.

Early ObservationsEarly Observations

1820:1820: Nasse of BonnNasse of Bonn– GermanGerman physician 1778-1851physician 1778-1851– Formulated observations on Formulated observations on

inheritance of hemophiliainheritance of hemophilia– ““Nasse’s Law” Nasse’s Law”

Transmitted by unaffected females to Transmitted by unaffected females to their sonstheir sons

Nasse CF. Arch Med Erfahr. 1(1820):385.

Early ObservationsEarly Observations 1828: 1828: The word “hemophilia” first appears The word “hemophilia” first appears

in a description of inherited bleeding in a description of inherited bleeding disorders by Physician Frederick Hopff at the disorders by Physician Frederick Hopff at the University of ZurichUniversity of Zurich

1840: 1840: First recorded case of hemophilia First recorded case of hemophilia treatment by transfusion written by Samuel treatment by transfusion written by Samuel Lane in Lane in The Lancet The Lancet 11

1893: 1893: First documentation of abnormal First documentation of abnormal prolongation of coagulation in capillary tube prolongation of coagulation in capillary tube in hemophilicsin hemophilics22

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: Early Observations: Other Highlights of the Early Other Highlights of the Early 1900s1900s

1911: 1911: Publication of “monumental review of Publication of “monumental review of pedigrees of families with bleeding disorders”pedigrees of families with bleeding disorders”11

1920-1930: 1920-1930: Hemophilia treatments published; Hemophilia treatments published; plasma for transfusions introducedplasma for transfusions introduced

1926: 1926: Erik vonWillebrand describes bleeding Erik vonWillebrand describes bleeding disorder affecting both sexesdisorder affecting both sexes

1937: 1937: IV administration of redissolved plasma IV administration of redissolved plasma precipitate shown to shorten blood clotting timeprecipitate shown to shorten blood clotting time22

1937:1937: First permanent blood bank established in First permanent blood bank established in USUS

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.

1940s1940s

Early to Mid-1940s:Early to Mid-1940s: Medical progress accompanies Medical progress accompanies warwar– Charles Drew sets standard for collecting, storing Charles Drew sets standard for collecting, storing

and transporting plasma under “battlefield and transporting plasma under “battlefield conditions”conditions”

– Edwin Cohn, Harvard biochemist, first to use Edwin Cohn, Harvard biochemist, first to use fractionation process to produce albumin in 1944fractionation process to produce albumin in 194411

– Albumin usefulness spurs research in blood Albumin usefulness spurs research in blood component therapy by “clotters” component therapy by “clotters”

– 1946-1947: 1946-1947: Hemophilia defect in plasma Hemophilia defect in plasma componentcomponent22

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.

1940s1940s

1948: 1948: A golden decade A golden decade for coagulation for coagulation research beginsresearch begins

Hemophilia Hemophilia Foundation Foundation established 6/15/48established 6/15/48

Hemophilic dog Hemophilic dog colony established: colony established: Chapel Hill, North Chapel Hill, North CarolinaCarolina

Smith N. A History of the National Hemophilia Foundation. New York: National Hemophilia Foundation, 1984.

©UNC Center for Thrombosis and Hemostasis

1950s1950s

First First recommendation recommendation for home infusion for home infusion

1959: First 1959: First hemophilia hemophilia treatment center treatment center in Rochester, NYin Rochester, NY

Smith N. A History of the National Hemophilia Foundation. New York:National Hemophilia Foundation, 1984.

Photos of Mary Gooley (above) courtesy of theMary M. Gooley Hemophilia Center, Rochester, NY

1950s1950s

Biggs R, et al. Br Med J. Dec. 27, 1952;1378. With permission from BMJ Publishing Group.

1950s1950s

1952: 1952: Evolution of the definition of hemophilia:Evolution of the definition of hemophilia:– A A blood clotting disorder affecting males with blood clotting disorder affecting males with

two possible major protein deficiencies: two possible major protein deficiencies: • FVIII - Hemophilia A FVIII - Hemophilia A • FIX - Hemophilia BFIX - Hemophilia B

– Thromboplastin generation test for measuring Thromboplastin generation test for measuring FVIII developedFVIII developed

– Coagulation cascade discoveredCoagulation cascade discovered

Langdell RD, et al. J Lab Clin Med. 1953;41:637-647.

1950s1950s

1958: 1958: First use of prophylaxis in Hemophilia First use of prophylaxis in Hemophilia A conducted in Sweden by Prof. Inga A conducted in Sweden by Prof. Inga Marie NilssonMarie Nilsson

1960s1960s

1960s:1960s: NIH grants create research climateNIH grants create research climate 1961: 1961: Hyland Laboratories begins work on FVIII Hyland Laboratories begins work on FVIII

concentrateconcentrate 1966: 1966: Peanut flour touted as treatment for Peanut flour touted as treatment for

hemophilia – hemophilia – Nature Nature 11

1. Nature. February 13, 1969. Vol. 185, No. 4711, pp. 469-470.

1960s1960s

1965:1965:Discovery ofDiscovery ofCryoprecipitateCryoprecipitateJudith Graham Pool, Judith Graham Pool,

MDMD

File photo courtesy of HANDI, NHF.

Pool JG, Shannon AE. N Engl J Med. 1965:273:1443-1447.

1960s1960s

1966: 1966: Hyland Hyland announces announces commercial commercial availability of FVIII availability of FVIII concentratesconcentrates

1969:1969: FIX FIX concentrate concentrate licensedlicensed11

1. Hoag MS, et al. N Eng J Med.1969;280(11):581-6.

1960s1960s

Continuous infusionContinuous infusion Predictable and sustained level over timePredictable and sustained level over time Cost savings due to decreasedCost savings due to decreased

– Laboratory evaluationsLaboratory evaluations– Clearance over timeClearance over time

Ideal replacement for surgical interventions Ideal replacement for surgical interventions and specific bleeding episodes in hemophilia 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.

1969: 1969: First hemophilia camp established First hemophilia camp established

1960s1960s

1970s1970s 1970s:1970s: Home infusion therapy: a commonHome infusion therapy: a common treatment practice treatment practice 1971:1971: von Willebrand’s factor identified¹ von Willebrand’s factor identified¹ 1974:1974: First successful immune tolerance² First successful immune tolerance² 1975: 1975: Federally funded comprehensive Federally funded comprehensive

hemophilia treatment centers initiatedhemophilia treatment centers initiated 1977: 1977: Mannucci discovers DDAVP increases Mannucci discovers DDAVP increases

FVIII and vWF levelsFVIII and vWF levels33

1. Zimmerman, TS, et al. J Clin Invest.1971;50:244-254.2. Brackmann HH, Lancet 1977; 2 (8044): 933.3. Mannucci PM. Lancet. 1977;1:869-872.

Regional Hemophilia Regional Hemophilia Treatment Center Treatment Center NetworkNetwork

1970s1970s

Revisiting use of Prophylaxis Revisiting use of Prophylaxis UK study – 9 boys with Hem A <1%UK study – 9 boys with Hem A <1%- Randomized, blinded, crossover studyRandomized, blinded, crossover study- Had target joints presentHad target joints present- Received 25% correction with FVIII or placebo once a Received 25% correction with FVIII or placebo once a

week, followed by week of restweek, followed by week of rest- Showed 15% reduction in bleeding episodes in 100 Showed 15% reduction in bleeding episodes in 100

day period (from 13.6 episodes to 11.6)day period (from 13.6 episodes to 11.6)- 66% decrease in bleeds in first three days of the 66% decrease in bleeds in first three days of the

weekweek Aronstam. 1976. Aronstam. 1976. Brit J Haematol. Brit J Haematol.

33:81.33:81..

1970s1970s

Transmission of blood-borne diseases:Transmission of blood-borne diseases:– Hepatitis B: HBVHepatitis B: HBV– Hepatitis non-A, non-B: Later called “C”Hepatitis non-A, non-B: Later called “C”– HIVHIV

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: HBVHepatitis B Virus: HBV

Lipid-enveloped DNA virus Lipid-enveloped DNA virus Replicates within liver cellsReplicates within liver cells Transmitted by exchange of Transmitted by exchange of

bodily fluids bodily fluids 90% recover with immunity; 90% recover with immunity;

10% develop chronic HBV of 10% develop chronic HBV of which 20-30% progress to which 20-30% progress to cirrhosiscirrhosis

Virion sensitive to heat and Virion sensitive to heat and solvent/detergentsolvent/detergent

1981:1981: Hep B vaccine plasma Hep B vaccine plasma derivedderived

1987:1987: Hep B vaccine Hep B vaccine recombinant licensedrecombinant licensed Electron micrograph of Hepatitis B

Virions courtesy of the CDC

The Price of The Price of IndependenceIndependenceNon-A, non-B (Hepatitis C)Non-A, non-B (Hepatitis C) recognized recognized

as transmissible via plasma-derived as transmissible via plasma-derived productsproducts– 1986: Commercial screening for non-A, non-1986: Commercial screening for non-A, non-

B hepatitis surrogate markersB hepatitis surrogate markers– 1989: Hepatitis C isolated1989: Hepatitis C isolated– 1990: Hepatitis C Ab testing of donated 1990: Hepatitis C Ab testing of donated

blood beginsblood begins

Hepatitis C Virus: Hepatitis C Virus: HCVHCV

Lipid-enveloped RNA virus Lipid-enveloped RNA virus Replicates within infected liver cellsReplicates within infected liver cells Transmitted by the exchange of bodily fluids Transmitted by the exchange of bodily fluids 85% or more with acute HCV infection 85% or more with acute HCV infection

progress to chronic hepatitisprogress to chronic hepatitis**

Virion sensitive to heat and solvent/detergent Virion sensitive to heat and solvent/detergent No vaccine availableNo vaccine available

* Seeff LB. Am J Med. Dec. 1999;107[6B]:10S-15S.

1980s1980s

MMWR July 16, 1982/31(27):365-367.

The Price of The Price of IndependenceIndependence

1983: 1983: Suspicion that HIV threatened the worldwide blood Suspicion that HIV threatened the worldwide blood supplysupply

April 1, 1983:April 1, 1983: Hemofil-T, first heat-treated FVIII concentrate in Hemofil-T, first heat-treated FVIII concentrate in the U.S.the U.S.

1984:1984: MontagnierMontagnier11 and Gallo and Gallo22 discover HTLV-3 (HIV) discover HTLV-3 (HIV) 1984:1984: Efficacy of heat treatment for viral inactivation Efficacy of heat treatment for viral inactivation

demonstrateddemonstrated 1984:1984: Recall of blood products initiatedRecall of blood products initiated 1985: 1985: ELISA test used to detect HIV antibodies among blood ELISA test used to detect HIV antibodies among blood

donorsdonors

1985:1985: Safety net: Safety net:

1. Barre-Sinoussi F, et al. Science 1983; 220(4599):868-71.2. Gallo RC, et al. Science 1984; 4;224(4648):500-3.

1. Donor deferral2. Viral inactivation methods3. HIV antibody testing

The Heroes We Care ForThe Heroes We Care For

Photo courtesy of Mary Lou Cygan, R.N., P.N.P.

1980s1980s

1990s1990s 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.

1990s1990s

Soucie JM, et al. Blood. 2000;96(2):437-442.

CharacteristicsCharacteristics HTC (%)HTC (%) Non-HTC (%)Non-HTC (%) PP

SeveritySeverity

MildMild 21.821.8 52.852.8 <.001<.001

ModerateModerate 24.224.2 26.726.7

SevereSevere 54.054.0 20.520.5

InhibitorsInhibitors 6.06.0 2.32.3 <.001<.001

Liver diseaseLiver disease 2.32.3 0.70.7 .002.002

HIV infectionHIV infection 31.131.1 17.117.1 <.001<.001

AIDSAIDS 8.28.2 5.95.9 .02.02

1990s1990s

Soucie JM, et al. Blood. 2000;96(2):437-442.

Mortality decreased Mortality decreased 40%40% in patients using a in patients using a comprehensive hemophilia treatment center comprehensive hemophilia treatment center (HTC(HTC))

““The finding that HTCs have a significant effect onThe finding that HTCs have a significant effect on

reducing mortality in patients with hemophilia supportsreducing mortality in patients with hemophilia supports

the effectiveness of such centers in providing the effectiveness of such centers in providing specializedspecialized

preventative care.”preventative care.”

1990s1990s

Prophylaxis recommendationProphylaxis recommendation PrimaryPrimary

– Early institution ~ 1-2 years with the aim of Early institution ~ 1-2 years with the aim of maintaining trough > 1%maintaining trough > 1%

– Longitudinal assessment of joint status essentialLongitudinal assessment of joint status essential SecondarySecondary

– Appropriate for intervention to prevent joint and Appropriate for intervention to prevent joint and other disease associated morbiditiesother disease associated morbidities

MASAC Recommendation #35. March 11, 1994.

2000s2000s

Gene therapy trials begunGene therapy trials begun Joint Outcome Study publishedJoint Outcome Study published11

National Pain SurveyNational Pain Survey Willetabs and Wilbrintin advertised as Willetabs and Wilbrintin advertised as

treatment for vWDtreatment for vWD

Manco-Johnson, et al. NEJM. 2007. Vol. 357:(6) 535-544.

Hemophilia A: Evolution of Hemophilia A: Evolution of TherapyTherapy

YearYear TherapyTherapy

19501950 Plasma (1-FVIII U/ml)Plasma (1-FVIII U/ml)

19661966 Cryoprecipitate (5-FVIII U/ml)Cryoprecipitate (5-FVIII U/ml)

19751975 Lyophilized concentrates (30-FVIII U/ml)Lyophilized concentrates (30-FVIII U/ml)

19831983 Heat treatment of lyophilized concentrates for viral Heat treatment of lyophilized concentrates for viral attenuationattenuation

19851985 Introduction of a solvent detergent for viral inactivationIntroduction of a solvent detergent for viral inactivation

19881988 Monoclonal antibody-purified FVIII concentrates with Monoclonal antibody-purified FVIII concentrates with heat or solvent detergent treatmentheat or solvent detergent treatment

19921992 Recombinant DNA products: 1Recombinant DNA products: 1stst generation generation

2000s2000s 22ndnd & 3 & 3rd rd generation recombinant productsgeneration recombinant products

Hemophilia B: Evolution of Hemophilia B: Evolution of TherapyTherapy

YearYear TherapyTherapy

19501950 Plasma (1-FIX U/ml)Plasma (1-FIX U/ml)

19751975 Lyophilized prothrombin complex concentrates or PCC Lyophilized prothrombin complex concentrates or PCC (30-FIX U/ml)(30-FIX U/ml)

19851985 Heat treatment of lyophilized concentrates for viral Heat treatment of lyophilized concentrates for viral attenuationattenuation

Development of a solvent detergent for viral Development of a solvent detergent for viral inactivationinactivation

19921992 Chromatographic/monoclonal antibody-purified FIX Chromatographic/monoclonal antibody-purified FIX concentrate with ultrafiltration and thiocyanate concentrate with ultrafiltration and thiocyanate treatmenttreatment

19971997 Recombinant DNA productRecombinant DNA product

The The FutureFuture Longer acting concentratesLonger acting concentrates Recombinant therapy for vWDRecombinant therapy for vWD Alternate route therapiesAlternate route therapies Gene transplantationGene transplantation Elimination of transfusion-associated infectionsElimination of transfusion-associated infections Understand and overcome inhibitor Understand and overcome inhibitor

developmentdevelopment Quality of life issuesQuality of life issues

– Elimination of joint morbidityElimination of joint morbidity– Optimizing the individual’s social and academic Optimizing the individual’s social and academic

performanceperformance

…the promise of achieving your potential

The Future…The Future…