Blood Transfusion and Blood Products

Blood has always had a cultural significance, symbolic of the essence of life; but the process of transfusion—replacing blood with blood—only became an accepted and reliable practice in the twentieth century.
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William Harvey’s demonstration of blood circulation in 1628 opened up the possibility of transfusion. In 1665 an English physiologist, Richard Lower, described the first successful transfusion between dogs. The first human transfusion came two years later: Frenchman Jean-Baptiste Denis transferred blood from a lamb to a sick boy, who reportedly recovered. The experiment was repeated but, following several deaths, was banned by 1678.

Interest revived in the nineteenth century when the role of blood as an oxygen transporter was understood. James Blundell at Guy’s Hospital in London used transfusions to revive women who hemorrhaged after childbirth. But there were two main problems. First, outside the body, blood would quickly clot, stopping free flow. Second, many patients had severe, sometimes fatal, reactions. Karl Landsteiner solved this second problem in 1901 with his discovery of blood groups. He noticed a human serum sample ‘‘clumped’’ the red blood cells from some people but not others. Using new immunological theories, Landsteiner realized agglutination was due to the presence or absence of specific antigens on the red blood cell. Some individuals have antigen A, some B, some both, and some neither, leading to four blood groups or types: A, B, AB, and O. Not all groups are compatible; mixing incompatible groups causes potentially fatal clumping. Landsteiner’s discovery would ultimately make blood transfusion safe (he was awarded the Nobel Prize for physiology in 1930 for this work), but clinicians initially ignored the importance. In 1908 Reuben Ottenberg introduced typing and cross-matching of donors and recipients, but compatibility testing was not immediately adopted. Improvements in surgery drove the early twentieth century reintroduction of transfusion in America. In 1902 Alexis Carrel reported the possibility of direct transfusion, sewing a donor’s artery to the recipient’s vein (anastomosis). George Crile pioneered the technique, carrying out over 200 animal transfusions before progressing to humans, but Carrel received the recognition following publicity describing a transfusion between a surgeon and his 5-day-old son.

Direct transfusion avoided problems of coagulation but required delicate and painstaking surgery. It was difficult to quantify the amount of blood transferred, which could be lethal. Other surgeons experimented with semidirect methods of transfusion. W. G. Kimpton and M.S. Brown, along with many others, developed specialized equipment using canola, syringe, needles, stopcocks, and valves. Coating vessels with paraffin wax minimized clotting. Coagulation was overcome in 1914; three doctors (Agote in Argentina, Hustin in Belgium, and Lewisohn in the U.S.) independently demonstrated that sodium citrate could be used as an anticoagulant. Adding small concentrations to blood did not harm the patient but prevented clotting. Indirect transfusion was now possible. World War I accelerated the pace of change. With increasing demand, the indirect method was perfected. Blood was collected in citrate–glucose solution, refrigerated and transported in bottles to the front lines. Transfusion spread from North America to previously skeptical Europe. By the war’s end, it was a practical and relatively simple treatment that saved thousands of lives. The focus then turned to donor recruitment. The need for blood typing became clear; rapid testing procedures allowed selection of appropriate blood. In 1921, Percy Lane Oliver set up the first transfusion service with the British Red Cross. It was a ‘‘walking donor’’ service in which volunteers of known blood groups were available on demand, donating blood wherever it was needed. The idea spread, and donor panels were set up in Europe, the U.S., and the Far East during the 1920s and 1930s. The first blood bank was established in 1932 at Leningrad Hospital in Russia.

The outbreak of World War II prompted another dramatic expansion in blood donation services. A huge logistical operation supplied blood to the front lines and to civilian casualties; by 1944 U.K. donors provided 1200 pints a day. Plasma, the yellow serum that carries red cells, became a common transfusion fluid, used to treat shock by restoring blood volume. Using Flosdorf and Mudd’s lyophilization process, plasma was freeze-dried. Removing water under high vacuum left a dry powder, stable for months. Adding sterile water reconstituted the plasma. Other plasma warwork had long-term impact. Edwin Cohn, from Harvard Medical School, developed a process of cold ethanol fractionation to break plasma down into components. The most important product, albumin, was isolated from Fraction V. Packaged in glass ampoules, this concentrated ready-to-use liquid had vital antishock capabilities. Other products were developed from fractions: gamma globulin, fibrin foam, and blood-grouping globulins.

The Plasma Fractionation Project expanded to an industrial scale, with collaboration between universities and pharmaceutical companies. After the war, civilian blood transfusion expanded. The U.K. Blood Transfusion Service was established in 1946, recruiting voluntary donors with the promise of a cup of tea. More controversially, donors in the U.S. were paid. Developments in blood typing and screening ensured compatibility. Over twenty genetically determined blood group systems were identified, including Rhesus positive and negative. Collection equipment improved as disposable equipment replaced glass flasks and rubber tubing. In 1950 Carl Walter introduced the plastic collecting bag, having experimented with polymers to find one suitably robust, inert, and immune to extreme temperatures. The new bags reduced contamination and allowed economical ultra-low temperature freezing of blood. Using cryoprotectants like glycerol, red blood cells were preserved for long periods, allowing stockpiling of rare blood types. Processing developments continued through the century. Today, blood is collected into 450-ml plastic packs with anticoagulant solution. Using a closed system of satellite bags, it is centrifuged with minimal risk of contamination. The red cells, platelets, and plasma components are separated into individual bags, ready for further processing. More than 17 preparations of blood components are available, including clotting factors (such as Factor VIII for hemophiliacs), and antibodies for vaccine production. Whole blood is used only rarely, but no part of a blood donation is wasted. The wide availability of blood components has facilitated dramatic advances in surgery. Blood transfusion is commonplace in hospitals and clinical blood transfusion is a specialty in its own right. In the U.K. alone, over 2.5 million units of blood are collected each year, and demand continues to rise. In the last two decades of the century however, there was concern about virus transmission through transfusion. Public scandals in France, Canada, and Japan, where patients and particularly hemophiliacs became infected with HIV as a result of transfusions, led to comprehensive monitoring at all stages of donation. Testing for HIV was introduced in 1986 and for hepatitis C in 1991. Blood labeling was internationally standardized in 1992.
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Artificial blood substitutes may be the future. Blood volume expanders and hemodilutants (isotonic electrolyte solutions) are already widely used. The search for an artificial oxygen transporter is underway. Possibilities include microencapsulated hemoglobin, recombinant hemoglobin, or perfluorochemical emulsions.