Current status of haemotherapy
Today's sources of blood components worldwide
Precisely aimed promotion and information, targeted motivation and selection of non-remunerated, healthy volunteer repeat donors form the foundation of a safe and secure blood product supply in highly developed countries. In most developing and transitional countries, by contrast, family, replacement and paid blood donors are still a significant source of blood components for transfusion according to the World Health Organization (WHO). Apart from the fact that the risk of transmitting blood-borne pathogens from these blood product sources is higher, sufficient stocks of safe blood can only be assured by regular donations from unpaid, voluntary blood donors. In addition, less than half of the 85 million whole blood donations worldwide each year come from the less developed regions where more than 75 percent of the world's population live. A donation for rate of less than 10 per 1,000 of the population per year is considered insufficient for the development of modern medicine. In developing and transitional countries, most blood components are used for obstetric complications and maternal and infant anaemia; in contrast, in developed countries, most blood components are destined to older patients undergoing complex cardiovascular surgery, or who have trauma or sepsis, or require supportive treatment because of malignancies.
Standards in procurement of safe blood products
A structured history of each blood donor, a medical interview and examination by a physician are not only helpful in excluding potential risks for recipients, but also serve to protect the health and well-being of donors. In addition to these important safety measures, laboratory tests play an integral part in ensuring blood safety. The laboratory work-up includes searches for blood-borne pathogens, which will be discussed later on, precise determination of blood groups (e.g. ABO, Rh and Kell systems) and demonstration of the absence of clinically relevant antibodies in donors' plasma.
European harmonisation of quality standards for blood donations, testing and component production, adequate use of blood components in clinical haemotherapy as well as increasing cost pressures in clinical care are aspects currently requiring great attention.
The safe and sufficient supply of blood that highly developed countries currently enjoy could be endangered by factors such as the aging of the population in Europe, globalisation, increased international travel, and the proposed establishment of a "blood market" in Europe. Novel approaches to advertising as well as donor marketing and efforts to foster altruistic attitudes in society are required to combat these trends. A sufficient supply of safe blood components is vital for modern societies and it remains to be seen whether this major requirement current supportive medical care can best be achieved by national Red Cross organisations, hospitals, private pharmaceutical companies, governmental organisations or, possibly, a combination of these. The question has arisen as to whether it is better to establish smaller, hospital-based blood donor services that can work closely with hospital staff or bigger entities that function like pharmaceutical companies and that are able to reduce costs through economies of scale.
Ensuring safe blood components by testing for pathogens and pathogen reduction
Blood-borne pathogens have been a challenge for transfusion medicine since the beginning of haemotherapy. Direct transfusion of whole blood was recognised early on as a potential cause of transmission of Treponema pallidum. Hygiene during the entire blood donation process, preparation, storage, delivery and transfusion has always been and will continue to be of paramount importance for transfusion safety. Routine screening of all blood products started in the 1970s (Table I). Serological screening for antibodies against or products of hepatitis B virus (HBV), such as HBsAg and, later on, anti-HBc, hepatitis C virus (HCV), human immunodeficiency virus (HIV 1/2), cytomegalovirus (CMV) and syphilis were established between the 1970s and 1990s. These regularly improved serological assays and combo tests are helpful in detecting clinically inapparent infections in donors. However, it very soon became clear that the diagnostic window for some infections is broad and that it would be worth establishing a feasible and efficient method for direct detection of transfusion-transmitted viruses, especially HCV, HIV and HBV.
Table I.
Blood donor laboratory screening in our blood donor services and year of introduction of the respective test into routine testing (in parentheses).
| Blood donor screening in the laboratory | |||
|---|---|---|---|
| By serological tests | By nucleic acid amplification testing (pool polymerase chain reaction) | ||
| HBsAg | (1975) | HIV | (1997) |
| TPHA | (1970s/1984) | HCV | (1997) |
| Anti-HIV 1/2 | (1985) | HBV | (1997) |
| Anti-HCV | (1992) | HAV | (2000) |
| Anti-CMV | (1995) | Parvovirus B19 | (2000) |
| Anti-HBc | (2006) | ||
Beginning in January 1997, our institute started to screen all blood donations for HCV, HIV and HBV1 by means of nucleic acid amplification testing (NAT) using a mini-pool polymerase chain reaction methodology developed in-house. In 2000, mini-pool polymerase chain reaction testing for hepatitis A virus and parvovirus B19 was added to this screening regimen (Table I). In 1999, NAT for HCV became mandatory in Germany. In 2004, the Paul-Ehrlich-Institute, in its capacity as an agency of the German federal government, added HIV NAT to this list.
The risk of HCV or HIV transmission by blood transfusion in Germany is currently extremely low. Hourfar et al. calculated the residual risk of virus transmission by transfusion using data from more than 30 million unpaid voluntary blood donations of the Red Cross tested in Germany2. The residual risk for HCV transmission by a blood product was estimated to be 1 in 10.88 million transfused units (95% confidence interval [CI]: 7.51 million to 19.72 million). The residual risk for HIV-1 was calculated to be 1 in 4.3 million transfused units (95% CI: 2.39 million to 21.37 million), while that for HBV was calculated to be 1 in 360,000 transfused units (95% CI: 0.19 million to 3.36 million). Since anti-HBc testing became mandatory as an additional serological screen for all blood donations in Germany in 2006, the residual risk of HBV transmission has decreased even more.
Given the number of blood products transfused in Germany each year -about 4.4 million red blood cell units, about 430,000 platelet concentrates and about 1 million packs of fresh-frozen plasma3- the calculated impact of NAT testing on blood safety has been considerable. In "real life", the results might even be better. Indeed, since 1999, when NAT for HCV became mandatory for blood screening in Germany, only one case of transfusion-transmitted HCV has been reported, whereas before cases were reported every year (Figure 1).
Figure 1.
Reports to the federal authority Paul-Ehrlich-Institute (PEI) of suspected transfusion-transmitted hepatitis C virus infections in Germany from 1990 to 2009 (according to M. Nübling, M. Funk and B. Keller-Stanislawski, PEI); * = case from: Kretzschmar E et al.; Vox Sang 2007; 92: 297–301.
One of the consequences of the reduction in transfusion-transmitted infections has been that hitherto undervalued risks of haemotherapy have become relatively more prominent. For example, bacterial contamination of platelet concentrates, most often due to normally innocuous resident flora from the donor's deep skin layers, is a rare complication, but potentially dangerous for immunocompromised recipients. Using culture methods to detect bacteria in platelet concentrates is cumbersome and expensive and currently only identifies about half of the contaminated products before they are transfused. Novel rapid bacterial detection tests are not yet widely used in clinical practice and do have some drawbacks. Incorporating bacterial testing into the rapid release and logistics of delivering platelet concentrations for transfusion is one of the tasks that still have to be solved in a satisfactory manner. Hence, novel techniques such as pathogen inactivation offer an alternative to test procedures, especially for platelet concentrates (Table II). Pathogen inactivation techniques are in the stage of being introduced into blood component production.
Table II.
Pros and cons of the reactive strategy of testing for blood-borne pathogens versus the proactive strategy of pathogen inactivation.
| Testing for pathogens | Pathogen inactivation |
|---|---|
| Pros | Pros |
|
|
| Cons | Cons |
|
|
Novel and re-emerging pathogens4 due to global warming, increases in international connectivity and the impact of globalisation require constant vigilance to avoid infectious disasters via the blood chain (Table III5). Testing for these pathogens requires a reactive methodology. Pathogen inactivation might provide a novel approach to solving these problems proactively (Table II).
Table III.
| 1980 | HTLV-I* |
| 1981 | Borrelia burgdorferi/Lyme disease |
| 1981/1982 | HTLV-III* (= HIV-1)/AIDS |
| 1982 | E. coli O157:H7 |
| 1982 | HTLV-II* |
| 1983 | Helicobacter pylori |
| 1986 | Cyclospora species |
| 1986 | HIV-2 |
| 1986 | Ehrlichia species |
| 1988 | HHV-6° |
| 1988 | Hepatitis E (Caliciviridae) |
| 1989 | Hepatitis C (Flaviviridae) |
| 1992 | Vibrio O 139 |
| 1992 | Bartonella hensellae |
| 1993 | Sin nombre virus |
| 1995 | Hepatitis G (Flaviviridae) |
| 1995 | HHV-8° |
| 1996 | variant Creutzfeld-Jakob Disease (vCJD) |
| 1997 | Avian Influenza Virus Type A (H5N1) "bird flu" |
| 1999 | West-Nile virus (Flaviviridae) in the USA. |
| 1999 | Nipah virus |
| 2003 | SARS (Coronaviridae) |
| 2003 | Monkeypox virus |
| 2004 | Metapneumovirus |
| 2005 | Chikungunya virus (Ile de la Réunion; Islands in the Indian Ocean) |
| 2006 | Chikungunya virus in France |
| 2007 | Chikungunya virus in Italy |
| 2008 | West-Nile virus in Italy and Hungary |
| 2009 | Influenza virus type A (H1N1) "swine flu" |
= HTLV: human T-lymphotropic virus;
= HHV: human herpes virus
Novel techniques and methods may, however, increase production costs although sharp increases in costs can be attenuated by skilfully implementing and exploiting the methods to economise in blood component production and testing. The German Red Cross blood donor services were among the first to introduce universal leucodepletion and were the first to implement NAT for HCV, HIV and HBV. Nevertheless, the overall costs for blood components in Germany are among the lowest in Europe and the Western world.
Adequate use of blood components
The demand for regular blood donations is driven by consumption of blood products. Therefore, the consumption end of the transfusion chain also needs to be addressed. The aging of Western populations and the potential for a significant net shortfall of blood components for transfusion in the next few decades makes it mandatory not only to motivate and manage donors optimally, but also to ensure that adequate use is made of scarce cellular blood components.
Training courses for nurses, technicians and physicians to teach or upgrade skills concerning transfusion indications, transfusion triggers, handling of blood components, storage and transportation are essential in this regard. Audits, both internal and external, help to ensure adherence to standard operating procedures and haemotherapy guidelines.
The European optimal use project, co-funded by the European Community, has recently prepared a manual summarising both the different activities in the European Community member states and coordinated plans for the future to use scarce blood components efficiently in day-to-day clinical practice.
"Bloodless medicine" and growth factors: reasonable aims in modern medicine?
Many experts are calling for a shift towards "bloodless medicine". Differences in utilisation rates for blood components in various European countries are not correlated with significant differences in either clinical care or mortality rates. In contrast to developing countries, higher usage of blood components in Europe does not necessarily translate into higher quality supportive care. However, evidence of any true benefit from "bloodless medicine" is lacking.
Appropriate use of blood products is a goal worth aiming for, as discussed above. Nevertheless, the risk of under-transfusion in some patients exists. Furthermore, in some European countries, policies of reducing allogeneic blood transfusion led to less advertising for and mobilising of healthy volunteer blood donors which then resulted in a dramatic drop in blood donations that endangers the blood supply in these countries.
Growth factors such as erythropoietin have been successfully used in patients with erythropoietin-deficient chronic renal diseases, but adverse events such as a potential increase in tumour growth and dissemination in cancer patients as well as an increase in thromboembolic events like deep vein thrombosis and pulmonary embolism are reasons for extra care. The use of growth factors has not led to the hoped for decrease in mortality in some patient populations.
Cellular therapies
Cellular therapy is a more recent field of increasing activity in transfusion medicine. Starting with the procurement of granulocyte concentrates for granulocytopenic patients with severe, untreatable infections and haematopoietic stem cells for stem cell transplantation in malignant and non-malignant diseases, cellular therapies have flourished.
Haematopoietic stem cells from bone marrow are used nowadays mainly for specific therapeutic approaches in often non-malignant diseases in paediatric patients. Formerly widely used in treatment protocols for malignant diseases such as leukaemia, they have now been replaced by peripheral haematopoietic stem cells obtained via apheresis from healthy volunteers pre-treated with granulocyte-colony stimulating factor. Umbilical cord stem cells are a promising source of haematopoietic stem cells even for adult patients. However, harvesting and storing these cells is expensive and their clinical application, at least in Germany, is infrequent.
Research and development in modern transfusion medicine
The safety and quality of standard blood components today are the highest ever. Nevertheless, further development of blood products is necessary. In the past decade, most blood donor services in Europe have implemented universal leucodepletion and pre-donation sampling. Novel pathogen reduction methods and algorithms for blood donor screening, as discussed in detail above, need to be evaluated, validated and implemented in daily routines.
Blood transfusion services in Europe are specialised pharmaceutical producers which are closely linked to the clinical application of their products. In Germany, blood components are considered to be pharmaceutical drugs. For specialists in transfusion medicine, it is not easy to find evidence-based recommendations regarding transfusion triggers or adequate support strategies for blood components in chronically transfused patients. Clinical studies sponsored by the blood transfusion services, possibly on a Europe-wide scale, are therefore urgently needed.
Specific cellular products, gene therapy and immunotherapy are novel aspects which will help to bring regenerative medicine and cellular therapy to blossom. Novel stem cell therapies in acute myocardial infarction and chronic heart failure are just two examples of the extraordinary developments currently underway in this field6,7.
Cytomegalovirus-specific T-lymphocytes can be harvested from selected donors by apheresis, enriched and then transfused into recently transplanted, still aplastic patients suffering from overwhelming cytomegalovirus infections. Initial clinical studies have provided very promising results. Other life-threatening complications such as fungal infections might also be targets for this platform technique.
Natural killer cells are another option for cellular therapy worthy of consideration. Natural killer cell lines have been shown to be efficient in killing tumour cells, but additional re-targeting of these natural killer cells might offer an even more potent weapon against tumour cells in the future.
Future challenges
Modern clinical transfusion medicine and haemotherapy are essential parts of today's medicine. The transplantation of solid organs, tissues and haematopoietic stem cells, tissue banking, and forthcoming cellular therapies all require complex approaches to diagnosis, procedures, and supply logistics in addition to a novel regulatory framework. Satisfactory solutions to all of these challenges have not yet been fully developed.
Synthetic or bioengineered cellular blood components show promise. However, it could be years or even decades before these products are ready to enter broad clinical use. Therefore, repeat volunteer unrelated blood donors will remain the major source of cellular blood components for the next decade at least.
Motivating potential blood donors, managing donors, e.g. temporarily deferred or inactive ones, and altruistic attitudes in society which enable us to provide a safe, predictable and secure blood supply, are therefore essential cornerstones of tomorrow's blood transfusion. Competition among different blood organisations, including private companies which pay for whole blood donations, might damage the altruistic attitude in society and leave us with a blood supply problem.
Activities to ensure the adequate use of scarce blood products in clinics must continue. Clinical counselling will probably become an even more important part of our daily work. On behalf of our patients, we must work to ensure that blood products are used adequately. This will also help to circumvent potential supply problems.
Close co-operation and scientific networking with industrial and clinical partners in tissue and organ transplantation, cellular therapy and other new areas of medicine are vital to the future of our field. However, funding for research and development, competition with the pharmaceutical industry over laboratory blood donor screening and new blood substitutes, as well as growth factors such as erythropoietin, thrombopoietin or granulocyte colony-stimulating factor provide some examples of the more problematic fields in this competition.
Competition is an important factor for the success of the European economy as well as in the scientific world. However, blood donations are gifts from healthy donors to patients who need them. The buying and selling of blood donations or a "blood market" should not be fostered by the European Union. On the other hand, policies are needed to define the framework within which competition in the healthcare market in Europe takes place. Harmonisation of blood donation and haemotherapy in Europe, reimbursement of blood donors, calculation of costs and pricing, a tendency to commercialisation of blood services leading to a competition for donors, a "donor and blood product market", Europe-wide blood product distribution including regions with different epidemiological backgrounds for blood-borne diseases and different levels of quality management are examples of currently unsolved problems which require the close attention of European politicians and experts in the field of transfusion medicine.
Conclusions
The safety and quality of blood products as well as the safety of the blood supply in Europe and other highly developed regions of the world are very good and better than ever before in history. This is not, however, the case in most developing or transitional countries, thus hampering the rapid development of modern medicine in those countries.
While the demand for blood products in Europe is growing, demographic changes will lead to a decrease in the proportion of the young in populations from which most of our current blood donors come. These demographic changes could lead to a shortage of blood products in the future, if not counteracted by modern donor management, recruitment of healthy people currently not donating blood and attempts to make the optimal use of precious blood donations. Such attempts have been successfully implemented by European projects.
Bioengineering and production of red cells, platelets and granulocytes are currently only feasible on a bench-scale. Although promising, there is probably still a long way to go and engineered cellular blood components are unlikely to enter into clinical use within the next decade. This approach will not, therefore, alleviate the predicted net shortfall in blood component supply in the coming years.
Development and production of novel cellular therapeutics are promising and challenging tasks for modern transfusion medicine. Although "zero risk" in cellular and gene therapy or haemotherapy is not possible, society strives for this and must, therefore, be willing to fund and support attempts to achieve it.
Footnotes
Presented in part at the XXXIX Convegno Nazionale di Studi di Medicina Trasfusionale (Milan, Italy, 9-12 June 2010).
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