WO1989004840A1 - Procede d'isolement du facteur viii de coagulation - Google Patents

Procede d'isolement du facteur viii de coagulation Download PDF

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Publication number
WO1989004840A1
WO1989004840A1 PCT/NO1988/000086 NO8800086W WO8904840A1 WO 1989004840 A1 WO1989004840 A1 WO 1989004840A1 NO 8800086 W NO8800086 W NO 8800086W WO 8904840 A1 WO8904840 A1 WO 8904840A1
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WO
WIPO (PCT)
Prior art keywords
factor viii
plasma
filter
blood
passed
Prior art date
Application number
PCT/NO1988/000086
Other languages
English (en)
Inventor
Ole-Jan Iversen
Kåre BERGH
Størker JØRSTAD
Gøril FASTING
Original Assignee
Fasting Biotech A.S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fasting Biotech A.S. filed Critical Fasting Biotech A.S.
Publication of WO1989004840A1 publication Critical patent/WO1989004840A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)

Definitions

  • This invention relates to a process of isolating coagulatio Factor VIII from blood.
  • Hemophili A is a hereditary bleeding disease due to the subject's lack of ability to synthesize a protein, Factor VIII, which is required for the coagulation of blood.
  • Factor VIII a protein that is required for the coagulation of blood.
  • the most important treating principle by bleedings occured with hemophili A subjects is the supplement of Factor VIII.
  • Factor VIII is isolated from plasma of healthy blood donators. By a usual blood donation about 200 ml plasma is obtained. The low concentration in the plasma makes a concen ⁇ tration of Factor VIII necessary before it can be used for treatment purposes. This is accomplished by cryopre ⁇ ipitation, i.e. the plasma is frozen down to -70°C for at least 24 hours and is subsequently slowly thawed. By this process part of the plasma proteins are presipitated and among them Factor VIII. Due to the heat lability of the protein, this procedure will, however, result in a substantial loss of Factor VIII activity (50-70% loss) .
  • a serious problem in connection with Factor VIII treatment is the risk of transmitting infections.
  • the chance that a Factor VIII concentrate prepared by the present methods may comprise virus such as hepatitis B, non A non B hepatitis or AIDS-virus is not to be overlooked. Measures to reduce infection risks have high priority.
  • Today heat treatment is used to inactivate virus, but this process also results in a substantial destruction of Factor VIII activity, rendering the total yield of a heat treatment doubtful.
  • the half life of Factor VIII is about 10 hours, and this means that the velocity of new synthesis is correspondingly high.
  • An increased risk of bleeding at the donator only occurs when the Factor VIII concentration is reduced to below 10% of the normal value. The consequence is that a blood donator may donate Factor VIII quantities far beyond the contents of 200 ml plasma obtained by an ordinary blood donation.
  • the principle resides in that the blood of the donator is passed through a filter, plasma separator, separating blood cells from plasma.
  • the blood cells are returned to the patient, whereas the plasma is passed through a filter 2, plasma filter, having a size of porousity retaining proteins of such size as Factor VIII ( oleculear weight 180.000).
  • Other plasma components such as e.g. albumin (65.000) will pass the filter and be returned to the patient.
  • filter l, the plasma separator has a porousity size retaining larger components than e.g. 20 nm, virus particles will not be able to pass the membrane, thereby preventing transmission of infection material with Factor VIII.
  • the aim of the present invention is thus to provide a process of isolating Factor VIII in blood plasma resulting in a better degree of recovery than previously and simultaneously reduce the risk of transmitting infections to the recipient.
  • process this is obtained by passing blood containing Factor VIII through a non- excluding first filter (plasma separator) retaining blood cells and possible infectious agents and further passing the plasma (filtrate) to an excluding second filter (plasma filter) retaining Factor VIII but being permeable to smaller components as e.g. albumin and collecting the Factor VIII enriched retentate.
  • a non- excluding first filter plasma separator
  • plasma filter plasma filter
  • the retentate is recirculated to the plasma stream between the first and second filter.
  • the present invention by leading the plasma from the plasma separator into a cooled container means from which the plasma is passed to a plasma filter which substantially retains Factor VIII but letting smaller components such as albumin penetrate.
  • the retained plasma (retentate) of the plasma filter is passed through a cooling device back to the container means wherein the plasma from the plasma separated initially arrives and is mixed with this, and is then passed to the plasma filter, the amount of plasma filtered through the plasma separator is substantially in volume corresponding to the filtrate volume from the plasma filter and subsequently after a desired time of operation the plasma of the recirculation circuit (the container means) being highly enriched of Factor VIII, is drained off.
  • a peltier element is preferably used as a cooling member in this circulation system.
  • this peltier element is run maintaining the plasma at a temperature of 3-5°C.
  • the temperature of the container means is kept at 3- 5°C during circulation in the system.
  • the plasma of the recirculation is run at a velocity of appr. 500 ml/min.
  • the filtrate from the plasma filter is passed through a heating element thereby obtaining a temperature of 37°C before being returned to the blood donator.
  • a recirculation system is used between filter 1, plasma separator and filter 2, plasma filter. This recirculation principle prevents clogging of the filter 2.
  • a cooling member is incorporated in the recirculation circuit enabling a temperature of e.g. 4°C in the recirculation circuit. This will have a stabilizing effect on a heat labile protein such as Factor VIII.
  • ASAHI filter AP05H ASAHI Medical Co., Tokyo, Japan
  • ASAHI filter AC 1760 filter II having a cut-off 10 5
  • a - bag having a volume of appr. 0,5 1 was incorporated in the recirculation circuit making a total plasma volume of the recirculation circuit of 0.7 liters.
  • the Factor VIII activity was measured by a Cephote ⁇ t (Nycomed A/S, Oslo, Norway) according to the method described by the producer.
  • the Factor VIII activity of plasma from a donator was 0.9 units/ml.
  • the Factor VIII activity of the recirculation circuit after 1,5 liter plasma having passed filter I was 1,8 units per ml, whereas the concentration of Factor VIII after 3 liter plasma having passed filter I was 2,5 units per ml. With an estimated plasma volume of 3 liter this means that about 65% of the Factor VIII activity is isolated by this method.
  • the analyses also indicate that the biological activity of Factor VIII is maintained during the isolation procedure.

Abstract

Procédé de concentration du facteur VIII, consistant à faire passer le sang contenant le facteur VIII par un premier filtre n'excluant pas le facteur VIII, puis par un second filtre d'exclusion retenant ledit facteur. On fait de préférence recirculer dans le courant de plasma s'écoulant entre le premier et le second filtre ce qui a été retenu par le second filtre.
PCT/NO1988/000086 1987-11-24 1988-11-22 Procede d'isolement du facteur viii de coagulation WO1989004840A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NO874882 1987-11-24
NO87874882A NO874882L (no) 1987-11-24 1987-11-24 Fremgangsmaate ved konsentrering av faktor viii.

Publications (1)

Publication Number Publication Date
WO1989004840A1 true WO1989004840A1 (fr) 1989-06-01

Family

ID=19890424

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NO1988/000086 WO1989004840A1 (fr) 1987-11-24 1988-11-22 Procede d'isolement du facteur viii de coagulation

Country Status (2)

Country Link
NO (1) NO874882L (fr)
WO (1) WO1989004840A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4141887A (en) * 1976-05-31 1979-02-27 Arnold Seufert Process and apparatus for the production of sterile filtered blood clotting factors
EP0041350A2 (fr) * 1980-05-29 1981-12-09 Japan Foundation For Artificial Organs Procédé et appareil pour l'élimination "on line" par filtration, de macromolécules d'un fluide physiologique
EP0044694A1 (fr) * 1980-07-18 1982-01-27 Kuraray Co., Ltd. Appareil pour la séparation ou l'échange de plasma par double filtration
US4402940A (en) * 1982-03-12 1983-09-06 Kuraray Co., Ltd. Method for treating blood plasma employing a hollow fiber membrane

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4141887A (en) * 1976-05-31 1979-02-27 Arnold Seufert Process and apparatus for the production of sterile filtered blood clotting factors
EP0041350A2 (fr) * 1980-05-29 1981-12-09 Japan Foundation For Artificial Organs Procédé et appareil pour l'élimination "on line" par filtration, de macromolécules d'un fluide physiologique
EP0044694A1 (fr) * 1980-07-18 1982-01-27 Kuraray Co., Ltd. Appareil pour la séparation ou l'échange de plasma par double filtration
US4402940A (en) * 1982-03-12 1983-09-06 Kuraray Co., Ltd. Method for treating blood plasma employing a hollow fiber membrane

Also Published As

Publication number Publication date
NO874882L (no) 1989-05-25
NO874882D0 (no) 1987-11-24

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