TRANSFUSION MEDICINE: THE BASIS AND THE FUTURE
“Blood, it’s in you to give”. So proclaims in a recruitment campaign by the Canadian Blood Services, hoping to encourage more Canadians to donate [1]. Undoubtedly, blood plays an eminent role in the normal function of all systems in the body. And in modern medicine, blood is used as a therapeutic modality in procedures such as surgeries, cancer treatments, and transplants. However, with an aging population, more of these procedures will be performed. This is why the demand for blood in Canadian hospitals increases by 8% [1]. But what is blood? What is exactly in blood that make them so useful and why is the demand for them is increasing annually in Canadian hospitals? This summary will answer these questions by focusing on the blood and the whole aspects of transfusion medicine – from the point you roll up your sleeve to donate blood to the point your blood concentrates are used clinically and surgically.
Your Blood, My Blood
In general, blood is composed of a cellular component and plasma component. The cellular component includes red cells, white cells, and platelets. The plasma component is the liquid portion of the blood and consists of various proteins and nutrients. Of one unit of whole blood collected, 55% is plasma, 40% is red cells and 5% platelets [1,2].
Mature red cells, the most prominent cells in whole blood, are non-nucleated and diploid in shape with an average diameter of 7.8 μm. Its membrane is composed of cytoskeletons that enable the red cell to pass through miniscule blood capillaries and between cell junctions [2].
Red cell formation and the maturation occur in the bone marrow, a process controlled by erythropoietin. With only a life span of 120 days, red cells one and only role in the circulatory system is to provide gas exchange for cells. Delivering O2 to vital organ systems and removing CO2 from organ tissues to the lung, red cells perform this mechanism by utilizing its hemoglobin, a complex globular protein carrying a prosthetic heme group. This heme group, which holds a ferrous (Fe2+) iron, is what carries the O2 in red cells [2].
As for white cells, they play a key role in the body’s defense mechanism. White cells in whole blood are present as neutrophils, monocytes, eosinophils and basophils. These phagocytic cells protect the host from invasion by engulfing foreign substances such as bacteria, viruses, and fungi. Like red cells, white cells are formed in bone marrow and the formation of each white cell lineage is controlled by their own particular growth factors [2].
Platelets, like red cell, are non-nucleated, small in size (~3 μm), and diploid in shape. Unlike red cells, platelets are composed of granules. Granules are either alpha or dense, each containing growth factors or clotting factors, respectively. Instead of maturation in bone marrow, platelets are released from megakaryocytes in the marrow by cytoplasmic fragmentation of megakaryocytes and only survive in the body for 10 days. They play a predominant role in the formation of a haemostatic plug at sites of vascular injury. This mechanism begins with adhesion of platelets to collagen exposed on damaged blood vessel where they are activated, releasing factors in their granules to increase the binding of more platelets to the site. Platelets finally aggregate to form a primary clot [2].
Plasma is composed mainly of water (~90%) along with nutrients and some vital proteins such as albumin, globulins, and clotting proteins, like fibrinogen and von Willebrand factor. The main role of plasma is to exchange vital materials and wastes from cells and supplies clotting proteins to the site of vascular injury [2].
The Purpose and the Risk
In the mid-17th century, Jean Baptiste Denis employed an instrument with two silver cannulae connected to a small reservoir and performed the first successful transfusion of animal blood into a human patient [2]. Centuries later, blood transfusion has evolved into a critical part of modern medicine. Besides acknowledging the risks of animal blood transfusion into human patients, we now have become more efficient in how we use the blood supply by transfusing only the blood component lacked in patients’ circulatory system instead of transfusing whole blood.
So, how is blood concentrate collected?
In general, there are two methods in which blood products are collected: whole blood donation and apheresis [2,3].
In the whole blood method, blood product is first collected as whole blood. Using centrifugation, whole blood components become separated and settle in the following order: red cells at the bottom, the “buffy coat” of platelet and white cells in the middle and the plasma on top.
Apheresis is similar to the whole blood collection except only the selected components are drawn off and the remaining components are returned to the donor’s circulation.
In the end, the blood products collected are red cells, platelets, and plasma. Plasma can be further fractionated into albumin, cryoprecipitate (rich in clotting factors such as fibrinogen, von Willebrand factor, and factor VIII) and intravenous immune globulin.
What is the purpose of blood transfusion?
The main reason to transfuse red cells to a human is to the restore the oxygen-carrying capacity. Thus, those who require red cell transfusion are those who have experienced large volume of blood loss, for example from trauma or surgery, or those who have hematopoietic malignancies [2,3,4,5].
Platelet concentrates are usually transfused to improve primary hemostasis and are mainly used to treat patients with a shortage of platelets or abnormal platelet functions [2,3,4,5].
Plasma protein concentrates are transfused to patients with hereditary coagulation factors deficiencies, such as, hemophilic (deficiency in Factor VIII) and von Willebrand’s disease (deficiency in vWF). Normally, either the fresh frozen plasma or direct coagulation factor concentrates (cryoprecipitate) are given to control bleeding in these patients [2,3,4,5].
What are some risks in transfusion medicine?
The level of safety has always been a concern in blood transfusion medicine. In recent years, safety awareness is heightened in three areas: infectious disease transmission risks, immunomodulation, and transfusion reaction [2,3].
Syphilis and hepatitis infections from transfusion are recognized well before. However, it is the discovery of human immunodeficiency virus (HIV) as a transfusion-transmitted agent which has raised the most attention from the lay public. Since this discovery, technology for protecting blood supply has improved. Screening tests targeting pathogens like HIV, Hepatitis B/C viruses and the bacterial causative agent for syphilis are routinely performed. These sensitive tests are generally immunoassay for detecting antibody targeting the pathogen. Despite the high efficacy of these screening tests, concerns are still high for HIV and hepatitis transmission through transfusion. Besides these classical infectious agents, infections from new and emerging pathogens like variant Creutzfeldt-Jakob disease are also possible [1,2,3,4,5].
Another challenge to the safety of blood transfusion is immunomodulation. According to a few studies, the transfusion of allogeneic blood to patients may lead to the down regulation of the immune system. This is shown in a case study which found higher incidences for postoperative infection in patients transfused with allogeneic blood compared to patients who have autologous transfusion. Beside the increase in infection, recurrence of cancer has also been linked to immunomodulation. Although the exact mechanism of the immunosuppression by allogeneic blood is not known, there is a suggestion that allogeneic transfusion leads to a decrease in T cell helper type 1 reaction cytokines which ultimately leads to the down regulation of cellular immunity [2,3].
Lastly, transfusion reaction is usually referred as the adverse reaction that the body has to the blood transfused. One transfusion reaction is acute hemolysis. This occurs when incompatible blood cells is transfused to a patient. In general, there are four types of blood in humans: A, B, AB and O. This is dependent on the antigens expressed on the red blood cells. In blood, there will be antibodies which target the non-self antigens expressed on the red cell surface. Because of the antibodies, problems can arise when transfusing a patient with the wrong type of blood. For example, a patient with Type A blood will have anti-B antibody and if Type B blood is transfused to the patient, the anti-B antibody will target and destruct the red cell transfused [2,3].
Another transfusion reaction is Transfusion-related acute lung injury (TRALI). TRALI is the most common adverse effect in blood transfusion (1 in 2000 transfusions) and the leading cause of mortality in transfusion medicine. Complications of TRALI include pulmonary edema resulting in respiratory distress, fever and hypotension [2,3].
What is next?
Indeed, blood transfusion can be risky, even with a strict criterion on blood donor selection. Its benefits, however, can not be overlooked. Nevertheless, because of the possibilities of disease transmission and adverse effect arising after transfusion, the search for a system that has no side effects is a priority in transfusion medicine. Currently, there are two proposed mechanisms: preoperative autologous blood donation and artificial blood. Each has its own advantages and disadvantages [2,3,6].
Preoperative Autologous Blood Donation (PABD) is the blood collection method where patient’s own blood is collected and utilized during surgery. This is a promising method since the need for allogeneic blood is minimized and therefore risk of adverse reactions is reduced. However, some concerns are still present. In addition to the expected risks of bacterial contamination, this method of blood collection is not suitable for all patients, especially for patients with significant systemic and blood-borne diseases [2,3,6].
Artificial blood is another strategy to minimize the use of allogeneic blood in surgery. Its sole purpose is to act as oxygen therapeutic, mimicking the oxygen-carrying capacity of red cells. There are two main areas of research for these red cell substitutes [2].
One is hemoglobin-based oxygen carriers (HBOCs). This line of research is essentially to modify hemoglobin allowing for prolonged renal clearance (the PEG hemoglobin) and better O2 affinity (the recombinant hemoglobin). This can be accomplished either by modifying the surface of purified hemoglobin with biocompatible polymers like polyethylene glycol (PEG) or by modifying the tetramer structure of hemoglobin, generating recombinant hemoglobin. One limitation to this strategy is the generation of free radicals causing toxicity in the body [2,6].
Perfluorocarbon, an inert chemical compound that can carry and release O2, is also considered to artificial blood composition. One major advantage of perflurocarbon is that its release and binding of O2 is unaffected by effects like pH and temperature. Thus, the gas carrying and delivering capability can be uniform even in changing environments like the body. Yet, toxicity again is a major concern for perfluorocarbon [2,6].
Conclusion
Blood transfusion can be lifesaving. However, at the same time, blood transfusion can lead to risky situation such as transfusion reaction, disease transmission and immunosuppression. Thus current research in transfusion medicine is to find a system that can reproduce the same benefit seen in blood transfusion but minimize the risk.
References
2. Spiess B, Spence R, and Shander A. Perioperative Transfusion Medicine 2nd Edition. New York, NY. Lippincott Williams & Wilkins. 2006.
3. Jabbour N. Transfusion-free Medicine and Surgery. Massachusetts. Blackwell Publishing Inc. 2005
4. Regan F, Taylor C. Blood transfusion medicine. BMJ 2002; 325: 143-146.
5. Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine: First of two parts blood transfusion. New End Journal of Medicine 1999; 340: 438-447.
6. Goorha YK, Deb P, Chatterjee T, Dhot PS, Prasad RS. Artificial Blood. MJAFI 2003; 59: 45-50.