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Plasma fractionation - medicines derived from plasma
| Which medicines are prepared from plasma and what is their function? In the nineteenth century, interest in the ‘watery’ fraction of blood rapidly increased. It proved to be a source of new components, which can be isolated from it. In 1888, the German scientist Hofmeister published articles regarding the behaviour and solubility of blood proteins. Using ammonium sulphate, Hofmeister separated fractions that he called albumins and globulins. The principle of his differential precipitation-separation technique is still applied today. During World War II, the physical chemist Edwin Cohn developed a method by which plasma can be divided in different fractions. Plasma proteins such as albumin could be obtained in concentrated form. Although various researchers later modified this separation process, Cohn’s original process is still applied in many places. After the war, new developments gained momentum. In 1964, the American Judith Pool accidentally discovered that if frozen plasma thaws slowly at a temperature just above freezing point, a deposit is formed that contains a large amount of clotting factor VIII. The discovery of this ‘cryoprecipitate’ as a means to obtain factor VIII was a breakthrough for the treatment of patients with the blood-coagulation disease haemophilia A. Nowadays, a large number of plasma proteins can be isolated and used as medicine.
Plasma fractionation For the preparation of medicines from blood, Sanquin Plasma Products requires large quantities of plasma. The demand for clotting factor VIII largely determines the quantity of plasma required. In 2000 and 2001, 238,000 and 232,300 litres of plasma respectively, were used for the preparation of plasma products. This was sufficient to meet the need for plasma-derived clotting factor VIII in the Netherlands. In addition, it enabled Sanquin Plasma Products to meet the need for other plasma products, including immunoglobulins, albumin and protease inhibitors. Some proteins occur in plasma in large quantities. For example, there is approximately 40 grams of albumin in one litre of plasma. However, the concentration of other proteins is very low. For example, there is less than one milligram of clotting factor VIII per litre of plasma, which means that the amount of albumin obtained during plasma fractionation is much larger than the amount of various clotting factors. The processing of all Dutch plasma produces over 6,000 kg of albumin per year, compared to several grams of clotting factor VIII. On average, it takes nine to ten weeks to process plasma into an end product. This is the actual time required to manufacture the product. Since the storage of plasma and stock management (see Seven steps to safety) must also be taken into account (as part of the measures taken to prevent viral contamination), in the end, it eventually takes approximately six months before the plasma product becomes available. In 1998, Sanquin concluded an alliance with the Belgian sister organisation the Central Fractionation Department (CAF) of the Belgian Red Cross. In co-operation with the CAF, Sanquin has achieved an increase in scale of manufacturing, enabling it to raise the efficacy and efficiency of the production process. In this way, we will be able to meet the demands for plasma proteins well into the future. Top Clotting factors
On top of the cryoprecipitate, a certain amount of plasma remains (cryo-poor plasma), from which clotting factor IX (Nonafact®) and prothrombin complex (Cofact®) are obtained. Clotting factor IX is an important coagulation protein, lacking in people suffering from the blood-coagulation disease haemophilia B. Like haemophilia A, haemophilia B is a chronic, hereditary disease associated with the X chromosome. The prevalence of haemophilia B in the Netherlands is 1.3 per 100,000 inhabitants, amounting to a total of approximately 200 patients. Administering Nonafact® helps to normalise blood coagulation in these patients. Cofact® is a combination of clotting factors II, VII, IX and X. This prothrombin-complex concentrate is suitable for clinical application, in particular for an immediate correction of the coagulation system. The main indication is for patients who require oral anticoagulation therapy for the treatment and prevention of thrombosis. During this therapy bleeding may occur, for example in the brain. This requires rapid action and Cofact® is given to the patient to accelerate coagulation. When such patient must undergo an emergency operation treatment with Cofact® is also essential. Top Protease inhibitors In the next fraction obtained by plasma fractionation protease inhibitors occur in high concentration. These proteins are able to inhibit protein-splitting enzymes (proteases), which are released during coagulation processes, aggregation of platelets and the activation of the complement system. Protease inhibitors prevent that these processes continue unabated. Isolated during plasma fractionation, the C1-esterase inhibitor protein (Cetor®) is administered to patients with a congenital or acquired deficiency of this protein. The lack of this protein causes recurrent episodes of subcutaneous swelling (angio-oedema) of the soft parts of the face, throat, limbs (hands and feet) and digestive tract, which may lead to serious shortage of breath and intestinal disorders. The hereditary form of C1-esterase inhibitor deficiency (hereditary angio oedema or HAE) is very rare and has a prevalence of 1 in 20,000-30,000. The acquired form (acquired angio oedema or AAE) occurs even less frequently, usually in patients with chronic diseases, such as auto-immune diseases, or malignant diseases. Unlike HAE patients, AAE patients do produce C1-esterase inhibitors, but these are largely destroyed by auto-antibodies to the C1-esterase inhibitor. Subsequent steps in the plasma fractionation process produce immunoglobulins and albumin respectively. For the preparation of these plasma proteins, fractionation using alcohol is the key purification process, known as alcohol or ethanol fractionation (see illustration). This method was developed during World War II by Edwin J. Cohn at Harvard University in Boston and is also known as Cohn fractionation. This method is based upon differences in the solubility of plasma proteins resulting from differences in the concentration of added alcohol. Additional key factors include variation of the temperature, the pH value and the ion strength. Top Immunoglobulins (gammaglobulins) In the Cohn fractionation process, the immunoglobulins are isolated first. These proteins (also named gammaglobulins) play a key role in the defence against infectious diseases. Immunoglobulins is a collective term for all the antibodies in the blood. They attach themselves to a pathogen, for example a bacteria. This enables other cells or molecules of the immune system to then kill and remove the intruder. Patients who are unable to produce (sufficient) immunoglobulins themselves have a compromised immune system, and as a consequence a weak defence against common pathogens. Immunodeficiency can be congenital as well as acquired, for example due to leukaemia or a bone-marrow transplant. These patients suffer from frequent infections. Regular administration of immunoglobulins, usually every three to four weeks, is required to prevent this. Patients with an congenital immunodeficiency (primary immunodeficiency) have to be treated with immunoglobulins throughout their life. The immunoglobulins produced by Sanquin can be administered either intravenously (Immunoglobulin I.V.) or intramuscularly (Immunoglobulin I.M.). Patients who do not lack immunoglobulins could also benefit from treatment with immunoglobulins. Various diseases that accompany certain immunological reactions and inflammations can be treated with the intravenous administration of immunoglobulins. These immunoglobulins are increasingly being (intravenously) administered to treat haematological diseases and a number of neurological diseases that may have been caused by an auto-immune reaction. Immunoglobulin I.M. contains many antibodies, particularly against the hepatitis A virus. For this reason, this product is frequently used to combat infections with this virus. People who travel to the tropics, in particular, run the risk of being infected with the hepatitis A virus. For this reason, Immunoglobulin I.M. is administered as a precautionary measure prior to their departure (see Hepatitis). Top Specific immunoglobulin preparations Specific immunoglobulin preparations are plasma products that consist mainly of antibodies against a single foreign material, cell or (micro-)organism. Sanquin manufactures specific immunoglobulin preparations against the Varicella zoster virus, the hepatitis B virus, toxin of the tetanus bacteria and the Rhesus D antigen on red blood cells. For this, plasma is needed from donors who are hyperimmune to these micro-organisms or the Rhesus D antigen. This plasma is primarily obtained by plasmapheresis. Specific immunoglobulin preparations are administered intramuscularly. Known as passive immunisation, the administration of specific immunoglobulins provides the body with specific antibodies, which it therefore does not need to develop itself. Accordingly, there is immediate protection, albeit for a relatively short period of time. Passive immunisation does not activate the immune system, unlike vaccination, which involves the administration of a weakened form or a part of the pathogen, inducing the immune system to produce antibodies. Thus, vaccination causes the body itself to make antibodies and instantaneously combat a later infection with the same pathogen. This is called active immunisation. The advantage of passive immunisation is that the pathogen is immediately captured and removed, while in the case of vaccination to develop antibodies against the pathogen takes time. For this reason, vaccination is used as a precautionary measure. Varicella Zoster Immunoglobulin Hepatitis B Immunoglobulin Tetanus Immunoglobulin 250 IE Anti Rhesus (D) Immunoglobulin Varicella Zoster Immunoglobulin
Top Hepatitis B Immunoglobulin Hepatitis B Immunoglobulin is isolated from the plasma of donors, who have been actively vaccinated with the hepatitis B vaccine. As a result of vaccination, their blood contains antibodies against the hepatitis B virus (HBV). These specific immunoglobulins are used to prevent HBV infection. HBV causes hepatitis B, a liver infection, which may cause such symptoms as fatigue, fever, reduced appetite, muscle and joint pain, nausea and vomiting. Hepatitis B is sometimes accompanied by jaundice, which causes the white of the eye and skin to turn yellow, urine to become darker and faeces lighter in colour. Jaundice is caused by liver damage, resulting from the virus multiplying in the liver. The occurrence, gravity and duration of the complaints vary from person to person. In approximately 10% of all cases, the virus remains in the liver, rendering the disease chronic. In these cases, the disease could cause the liver to wither (liver cirrhosis) or result in liver cancer. Hepatitis B Immunoglobulin is administered to patients who have been infected with HBV-positive blood and have not been vaccinated against HBV before or who have not yet completed a course of vaccination or who are unable to produce sufficient antibodies against HBV. In such cases, the administered HBV antibodies must ensure that the virus is immediately removed. There is a risk of contamination if, for example, somebody has pricked him or herself with an object that may be contaminated with HBV. Such accidents occur in professions such as nursing, where people may come into contact with contaminated needles, or those who work in sanitation services, who run the risk of contact with contaminated waste. Top Tetanus Immunoglobulin 250 IE Tetanus is characterised by muscle spasms, preceded by pain and muscle stiffness. The muscle spasms usually start in the masseter muscles, after which they spread to the muscles of the trunk, via the neck and to the stomach. The disease is caused by infection with the tetanus bacteria Clostridium tetani. The (neuro)toxin released by this bacteria enters the central nervous system via the nerves, which results in the muscle spasms. Tetanus Immunoglobulin 250 IE is isolated from plasma of donors who have been actively vaccinated with the Tetanus vaccine or DTP (diphtheria-tetanus-polio) vaccine. As a result of these vaccinations, the donor blood contains antibodies to the tetanus toxin. These specific immunoglobulins are used to treat infection with Clostridium tetani and, prophylactically, as passive immunisation in case that a wound carries the risk of infection with Clostridium tetani. Such a risk is particularly high with bite, stab and bullet wounds. In addition, wounds that have been contaminated with soil, waste and animal faeces could be infected with Clostridium tetani and the administration of Tetanus Immunoglobulin 250 IE is then required. Together with the administration of Tetanus Immunoglobulin 250 IE, a course of active immunisation is started by the simultaneous administration of Tetanus vaccine. Top Anti Rhesus (D) Immunoglobulin The Rhesus D blood group antigen is present on the red blood cells of 84% of the Western population. Subjects who do not have the Rhesus D antigen (Rhesus D-negative subjects) in a high percentage of cases, form antibodies against it, when Rhesus D-positive red blood cells enter their circulation. This occurs when Rhesus D-positive red blood cells are transfused into such a patient or when a Rhesus D-negative woman is pregnant of a Rhesus D-positive foetus. Therefore, no Rhesus D-positive blood may be transfused to Rhesus D-negative patients. When a Rhesus D-negative woman is pregnant of a Rhesus D-positive foetus, Rhesus D-positive red blood cells of the child may enter the circulation of the mother. This occurs mainly during childbirth. Some red blood cells may be transported to the mother in the last three months of pregnancy but in only about 10% of cases the number of transported cells is sufficient to induce the formation of anti-Rhesus D antibodies. Thus, anti-Rhesus D antibodies are nearly always formed after the child is born. The anti-Rhesus D antibodies then formed may quickly increase in quantity when the mother again becomes pregnant of a Rhesus D-positive foetus, because only few red blood cells are needed for this, so-called secondary immune response. The anti-Rhesus D antibodies will pass into the circulation of the Rhesus D-positive foetus and cause lysis (destruction) of the red blood cells of the foetus. This leads to the disease “haemolytic disease of the foetus or new-born”, a serious disease, which may be fatal. To prevent the formation of anti-Rhesus D antibodies in the mother, and thus to protect a subsequent Rhesus D-positive child from haemolytic disease, Anti-Rhesus (D) Immunoglobulin is given to a Rhesus D-negative mother immediately after she gave birth to a Rhesus D-positive child, a procedure called immunoprophylaxis. The anti-Rhesus D antibodies bind any Rhesus D-positive red blood cells in the mother’s circulation, which leads to immediate elimination of these cells. Thus, the formation of anti-Rhesus D antibodies is prevented. Postnatal immunoprophylaxis (after the birth of the child) was introduced in the Netherlands in 1969. In this way the formation of anti-Rhesus D is prevented in the vast majority of cases. However, in some cases enough Rhesus D-positive red blood cells enter the mother’s circulation during the last three months of pregnancy, to induce the formation of anti-Rhesus D before the child is born. To prevent immunisation also in these cases, prenatal immunoprophylaxis was started in 1998: Anti-Rhesus (D) Immunoglobulin is also administered in the 30th week of pregnancy. It is also given to the mother after bleeding from the vagina during pregnancy, after an examination of the foetus (i.e. amniocentesis, chorionic villus sampling) and after abortion of a Rhesus D-positive foetus. Anti-Rhesus (D) Immunoglobulin is isolated from the plasma of donors who have produced such antibodies. Since transfusions of Rhesus D-positive red blood cells are not given to Rhesus D-negative patients, these donors are either Rhesus D-negative women who were immunised as a result of pregnancy, or male donors who are deliberately immunised by injections of Rhesus D-positive red blood cells. A group of dedicated plasmapheresis donors supply the anti-Rhesus D for immunoprophylaxis. Top Albumin The last fraction obtained in the plasma fractionation process is albumin, the molecule present in the highest concentration in blood plasma. As it cannot leave the capillaries in healthy persons, it plays a key role in maintaining oncotic pressure in the blood vessels. Oncotic pressure is the force which draws water from a less concentrated solution to a more concentrated solution through a selectively permeable membrane. The albumin concentration is higher in the blood stream than outside it. As a result water is drawn into the blood vessels. Albumin attracts water and ensures that it remains in the blood vessels and does not leak to the tissues. As a result, osmotic equilibrium is created in which the hydrostatic pressure on the blood vessels is equal to the osmotic suction (by albumin) from inside the blood vessels. This prevents on the one hand that too much water passes from the blood stream into the tissues and on the other, that too much water flows into the blood stream. In this way, the amount of water in the blood stream remains almost constant. In addition, albumin is responsible for the transport of substances in the blood, both of the body as well as foreign substances, such as medicines. Albumin’s third key function is to maintain the fluidity of blood. Albumin is administered to treat and prevent various forms of shock, for instance when, due to blood loss or vasodilatation, the volume of the circulating blood is insufficient to ensure adequate blood flow to the tissues. This may be the result of severe bleeding, for example as a result of surgery, burns or blood poisoning (sepsis). Sanquin supplies two albumin solutions, namely Pasteurised Plasma Protein Solution (containing 4% albumin) and Cealb® (containing a 20% albumin solution). Top |