Transfusion Medicine and Hemostasis. Clinical and Laboratory Aspects

925 Pages·2013·16.197 MB·English

by  Beth H. Shaz, Christopher D. Hillyer, Charles S. Abrams and Mikhail Roshal (Eds.)

C H A P T E R 1
Blood Banking and Transfusion Medicine –
History, Industry, and Discipline
Christopher D. Hillyer, MD
A safe, reliable, and available blood supply is critical to the function of complex
healthcare systems worldwide. Over the past 100 years, blood transfusion has grown
from the transfusion of small amounts of fresh whole blood, to one of the most
common therapeutic medical practices. Since approximately 1980, blood banking
and transfusion medicine is a board certifiable subspecialty by the American Board of
Pathology.
History of Blood Transfusion: History of blood transfusion is part of the fabric
of the history of humankind, including religion and superstition as well as science;
ranging from circulating humors to modern medicine. Few, if any, other substances
cause the same emotions, have the same associations, lead to the same fears, or have
found as many ways into our common parlance and lexicon. Indeed, blood transfusion
and blood-letting (now called therapeutic phlebotomy and apheresis) are some of the
oldest and most common medical practices.
Early Transfusions: The record of man’s attempt to treat suffering and disease by
blood transfusion extends back at least to 1667, when Jean Denis published in the Phil-
osophical Transactions his experience in Paris with transfusing lamb blood (because of
its presumed soothing qualities) to an agitated man (resulting in hemolytic transfusion
reaction). In 1818, Dr. James Blundell was the first to successfully transfuse human
blood into a patient with post-partum hemorrhage. Blundell recognized that he was
replacing lost blood volume, not providing a ‘vital force’. Advances, some of which are
described below, have allowed the development of modern blood banking and transfu-
sion medicine.
Blood Groups: Dr. Karl Landsteiner published, in 1900, the first of a series of papers
demonstrating presence of the ABO blood group system, stating that:
‘the serum of healthy men will agglutinate not only the red cells of animals, but
also often those of other individual humans.’
Although the use of this information to improve the safety of transfusion began
within a few years, it was not until about 1920 that ABO testing was regularly used.
The Rh blood group system was discovered during 1939–1940 by Landsteiner,
Weiner, Levine and Stetson, explaining the cause of many unexpected transfu-
sion reactions. In 1945, Coombs, Mourant, and Race described the use of anti-
human globulin sera to detect IgG antibodies in compatibility testing (unaware that
Transfusion Medicine and Hemostasis. http://dx.doi.org/10.1016/B978-0-12-397164-7.00001-X
Copyright © 2013 Elsevier Inc. All rights reserved. 3
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Christopher D. Hillyer, MD
Moreschi had described the use of such sera in 1908), thus providing the still-used
Coombs test.
Blood Storage: Direct transfusion (donor artery anastamosed to recipient vein)
was performed by Alexis Carrel in 1908, and direct transfusion using a three-way
stopcock was used up to World War II. While the use of sodium citrate as an antico-
agulant was considered as early as 1914 and used (with glucose, by Rous and Turner)
on a small scale during World War I to set up blood depots before a battle, blood
could be typically stored for only a few days. In 1943, Loutit and Mollison developed
acid citrate dextrose (ACD) solution, allowing storage of blood for weeks, facilitating
the ‘banking’ of blood. In addition, the acidification of the anticoagulant-preser-
vative solution allowed it to be autoclaved, and reduced the occurrence of bacterial
contamination in storage solutions.
Blood Derivatives: The cold ethanol fractionation process, allowing plasma to be
broken down into albumin, gamma globulin and fibrinogen, among other proteins,
was developed by Edwin Cohn in 1940 (called Cohn fractionation). This allowed
fractions such as albumin to be used as a volume expander, and the fibrinogen
fraction (containing factor VIII) to be used to treat hemophilia A. Fibrinogen, as
a component, fell into disuse because of the risk of hepatitis B, and treatment of
hemophilia was limited to fresh frozen plasma. When Pool and Shannon recognized,
in 1961, that the precipitate (cryoprecipitate) that formed when plasma was thawed
in the cold contained factor VIII, they revolutionized the treatment of hemophilia
A. In 1985, dry-heated, lyophilized factor VIII and IX concentrates became avail-
able. Genetically engineered (recombinant) factor VIII became available in 1993 and
factor IX in 1998. Most recently factor products are engineered without any human
components.
In 1967, a concentrated Rh immune globulin was introduced commercially, begin-
ning the gradual reduction and ultimately the near elimination of Rh hemolytic disease
of the fetus and newborn.
Blood Component Therapy: Introduction of plastic bags as a replacement for
glass bottles by Walter and Murphy for the collection and storage of blood in 1950
allowed the development of component therapy, with the use of refrigerated centri-
fuges to separate components by density, and pre-collection attached satellite bags to
store the prepared components. Concentrated blood platelets, prepared from whole
blood, were recognized as useful for the treatment of thrombocytopenia by 1961, and
platelets for transfusion were collected by apheresis by 1972.
Apheresis: In the 1950s Cohn designed a centrifuge to separate cellular components
from plasma. Through the work of engineers, inventors, physicians, and operators, the
advanced instrumentation for apheresis developed. The development of donor aphere-
sis allowed collection of therapeutic doses of platelet and granulocyte components, and
more recently collection of two red cell products from a single donor and the collec-
tion of sufficient volumes of plasma for further manufacturing into factor concentrates,
albumin, immunoglobulin, and other components. Full automation of therapeutic
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Blood Banking and Transfusion Medicine – History, Industry, and Discipline
apheresis devices has expanded and simplified the use of this modality, which is vital
to the treatment of many diseases (e.g. thrombotic thrombocytopenic purpura, sickle
cell disease).
Adverse Effects of Transfusion: In the 1960s, blood banks became increasingly
aware that paid donors were associated with higher rates of hepatitis transmission,
and by 1970 the slow and difficult transition to an all-volunteer blood supply in the
US had begun. In 1971, commercial testing for hepatitis B surface antigen began, and
further reduced the rate of post-transfusion hepatitis. A decade later, in 1985 and
about two years after transfusion-transmitted HIV was described, a test for the HIV
antibody was introduced. By 1990, testing for hepatitis C became routine and soon
after HIV antigen testing was introduced. By 2000, most blood collection facilities in
the developed world had adopted nucleic acid testing for HIV and HCV, thus further
reducing the residual risk of transfusion-transmitted HIV and HCV to <~1:2,000,000
screened units. Since that time, there has been a growing recognition of the trans-
missibility of infectious agents, such as prions (agent of new variant Creutzfeldt-
Jakob disease), West Nile virus and Trypanosoma cruzi (agent of Chagas’ disease),
and approaches to protect the safety of the blood supply from each of these have
been implemented. In some cases, new tests have been developed. In others, the blood
components have been treated to minimize risk of infection with pathogen reduction
technologies, though none of these technologies is currently approved for US use. In
still other disease conditions, those donors at risk for transmission of a given agent
have been deferred.
Over the past 25 years, noninfectious complications of transfusion also became
apparent, such as febrile non-hemolytic transfusion reactions and transfusion asso-
ciated graft versus host disease (TA-GVHD). In 1970, Graw et al. used irradiation to
prevent TA-GVHD, and in 1962, Greenwalt et al. demonstrated leukocyte reduction
filters prevented febrile reactions. Widespread use of leukoreduction started in the late
1980s and moved to become a customary blood center prestorage processing step in
the 1990s in most of the developed world. Serious non-infectious hazards of transfu-
sion still exist, and include ABO incompatible transfusion, transfusion-associated cir-
culatory overload, transfusion-related acute lung injury (TRALI), amongst others. For
many of these complications mitigation strategies have been successfully implemented.
Blood Pipeline: The provision of blood is best seen as a continuum or pipeline
‘from vein to vein’ – that is, from the vein of the donor to the vein of the recipi-
ent (Figure 1.1). From a safe practices standpoint and the view of federal regulators,
including the Food and Drug Administration (FDA), blood banking and transfusion
medicine is not just ‘from vein to vein’ but rather ‘from vein to vein and back’. This
allows for tracking of products transfused to a particular recipient ‘back’ to a given
donor, and thus determination of infectious disease transmission and other donor-
specific complications such as TRALI. The blood industry is collectively the business
units which relate to the pieces of the pipeline, while the discipline is the medical field
that relates to the many processes in the blood pipeline. The industry and discipline
have expanded beyond this pipeline to related fields, such as cellular therapies, thera-
peutics and coagulation.
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Christopher D. Hillyer, MD
Blood center Hospital
Imports Loss Loss
1 2 3 4 5 1 2 3 4
Reference Reference
Testing Control limit Control limit
1. Bookings and collections 1. General inventory
2. Manufacture 2. Crossmatched
3. Labeling 3. Issued
4. General inventory 4. Transfused
5. Distributions
FIGURE 1.1 The blood pipeline.
Blood Industry: The blood industry includes manufacturers (also called ven-
dors) of information systems, reagents, appliances and devices used by blood estab-
lishments, as well as the blood establishments themselves, including blood banks
and transfusion services. Vendors have also established an organization called the
Advanced Medical Technology Association (AdvaMed). Indeed, AdvaMed has taken
a leadership role in a number of areas, including defining appropriate corporate-
customer relationships to be in compliance with federal trade, financial and tax
regulations, and advancing the understanding of the challenges facing the industry
as regards government and third-party insurer reimbursement for blood and blood
components.
Discipline of Blood Banking and Transfusion Medicine: Over the past 25
years, blood banking and transfusion medicine has expanded to include a number
of related laboratory disciplines, services and therapeutics, depending in part on the
degree of complexity of the institution in which it is housed. These may include peri-
operative transfusion (perioperative autologous donation and cell salvage), thera-
peutic apheresis and phlebotomy, coagulation or specialized laboratories, hospital
tissue banking, and cellular therapy – which itself may include the collection, pro-
cessing, storage and distribution of human hematopoietic progenitor cell (HPC)
products, pancreatic islet cells, and related minimally and highly manipulated cells.
While credentialed as a single entity, blood banking and transfusion service terms
have increasingly come to have different meanings (transfusion medicine encom-
passing both terms).
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Blood Banking and Transfusion Medicine – History, Industry, and Discipline
Blood Banking Defined: Blood banking now typically refers to the collection,
processing, storage and distribution of whole blood and apheresis-derived blood and
blood components at a blood collection facility, defined by the FDA during registration
or licensure as a community blood bank, although a small percentage of units are
collected in the hospital setting, defined by the FDA as a hospital blood bank. Chapters
4–17 are dedicated to ‘blood banking’.
Transfusion Service Defined: The transfusion service most often connotes
pretransfusion and compatibility testing; post-manufacture processing, includ-
ing irradiation, washing and volume reduction; and administration of appropri-
ate products to the appropriate patients at the appropriate time. The transfusion
service thus occurs predominately in hospitals, usually under the FDA designation
at registration as a hospital transfusion service. The AABB Standards define these
activities as simply a ‘transfusion service’, since a number of blood centers will also
perform these functions or offer these services. The transfusion service is also typi-
cally responsible for consultation to clinicians regarding complex transfusion and
coagulation issues, the choice of specialized products including recombinant and
human-derived coagulation factor concentrates, intravenous gammaglobulin and
albumin, the development of guidelines, the review of blood component therapy
through audits and patient blood management. Chapters 18–87 are dedicated to
‘transfusion service’.
Centralized Transfusion Services: In some locations, perhaps most notably
Pittsburgh and Seattle, a single corporate entity staffs and serves as both the blood
collection facility and the hospital transfusion service. This model, referred to as the
centralized transfusion service, has a number of real or potential advantages, includ-
ing having a database of patient blood type and antibody history, centralized tracking
of blood components and physician consultation, and the ability rapidly and easily to
move blood components in order to service areas of increased need or shortage.
Structure of Blood Banks and Transfusion Services: Worldwide, the pre-
dominant structure of blood banks and transfusion services is as a national system,
often with organizational reporting to the Ministry of Health, likely via a national
countrywide medical system. One example is the UK National Blood Service. In
other countries the national blood service predominates but is not exclusive, and
some fragmentation or sharing of responsibilities exists – such as within the South
African National Blood Service and the National Blood and Transfusion Service of
Tanzania. National blood and transfusion services have traditionally been well posi-
tioned to formulate nationally adopted clinical guidelines for transfusion and estab-
lish hemovigilance programs.
US Structure of Blood Banks and Transfusion Services: A national blood
and transfusion service does not exist in the US, nor do any blood centers or trans-
fusion services (exclusive of the US Department of Defense) report organizationally
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Christopher D. Hillyer, MD
or legally to the federal government. Instead, a nationwide network of blood centers
has evolved including some blood systems, the largest of which are American Red
Cross Biomedical Services (ARC; Washington, DC) and Blood Systems, Inc. (BSI;
Scottsdale, AZ). In addition, many other blood centers exist as community blood cen-
ters and are highly regarded within their locale. These blood establishments account
for approximately 95% of the US blood collected and distributed, and are often
members (in a variety of different configurations) of several trade, procurement
and/or professional organizations, including America’s Blood Centers (ABC), Blood
Centers of America (BCA) and AABB. Internationally, US blood establishments
interrelate through organizations such as Alliance of Blood Operators (ABO) and
European Blood Alliance. The remaining 5% of blood is collected in hospitals, which
must be registered with the FDA as hospital blood banks unless meeting certain require-
ments allowing for non-registration.
In the US, the formulation of clinical guidelines for transfusion has in many
cases been accomplished by medical services that use large amounts of blood prod-
ucts, such as the American Society of Clinical Oncology regarding platelet trans-
fusion guidelines, and the Practice Guidelines for Blood Component Therapy by
the American Society of Anesthesiologists – although recently AABB has published
guidelines for plasma and red blood cell transfusions. Since 2006 AABB, with a
number of public and private organizations, has developed a hemovigilance sys-
tem for the monitoring of recipient adverse reactions and quality control incidents
related to blood transfusion, with broadened hegemony to include collection of
adverse events to donation and administration of blood, tissues, cellular therapies
and organs, termed biovigilance.
Medical Specialty of Blood Banking and Transfusion Medicine: Blood
banking and transfusion medicine is presently board certified in the US by the
American Board of Pathology. In order to be eligible for board certification, a
1-year ACGME-accredited blood banking and transfusion medicine fellowship is
required. One pathway to fellowship is via a residency in clinical pathology or a
combined anatomic pathology/clinical pathology program. However, a broad range
of training can allow a physician to be eligible, including internal medicine, pediat-
rics and anesthesiology, and adult and pediatric hematology. More information can
be obtained at www.abpath.org. Most transfusion medicine fellowships reside in
university and related medical centers, though some blood centers have particularly
excellent programs.
Subspecialties within Blood Banking and Transfusion Medicine: There are
no specifically defined subspecialties within the blood banking and transfusion
medicine discipline, though board-certified transfusion medicine specialists will
often become focused in either blood center or hospital transfusion service opera-
tions (see Chapters 4 and 18). Recent recognition of the specialized needs, processes
and technologies required for optimal transfusion of the pediatric patient has led
some to ask whether there should be specialized centers of excellence and/or train-
ing in pediatric transfusion medicine. Additionally, a number of individuals have
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Blood Banking and Transfusion Medicine – History, Industry, and Discipline
concentrated their clinical and academic efforts in a variety of more specialized
areas, including the transfusion of the patient with sickle cell disease, in ensuring
appropriate blood use (termed patient blood management) and cellular therapies
including regenerative medicine.
Recommended Reading
AuBuchon JP, Whitaker BI. (2007). America finds hemovigilance! Transfusion 47,
1937–1942.
Carson JL, Grossman BJ, Kleinman S et al. (2012). Red blood cell transfusion: a clinical
practice guideline from the AABB. Annals of Internal Medicine 157, 49–58.
Hillyer CD, Mondoro TH, Josephson CJ et al. (2009). Pediatric Transfusion Medicine
(PTM): development of a critical mass. Transfusion 49, 596–601.
MacPherson J (ed.). (2007). The role of blood centers in transfusion recipient care.
Second Joint Conference of America’s Blood Centers and the European Blood
Alliance, 13–14 November 2006, London, England. Transfusion 47, S101–S204.
Roback JD, Caldwell S, Carson J et al. (2010). Evidence-based practice guidelines for
plasma transfusion. Transfusion 50, 1127–1239.
Shaz BH, Hillyer CD. (2010). Transfusion medicine as a profession: evolution over the
past 50 years. Transfusion 50, 2536–2541.
C H A P T E R 2
Quality Principles in Transfusion Medicine
Eva D. Quinley, MS, SBB, CQA (ASQ)
The meaning of the term ‘quality’ continues to evolve over time. Initially, quality
was centered on quality control, sampling and testing, but with increasing attention
from governmental agencies, including the US Food and Drug Administration (FDA),
and focus from organizations such as AABB in the early 1990s, quality became a dis-
cipline of its own. For a time, ‘quality’ became synonymous with ‘compliance’, that is,
adherence to documented regulations and standards that defined and influenced the
activities and priorities of quality departments. Then, accrediting organizations such as
AABB promulgated quality system elements and standards for facilities to follow. Some
facilities sought to become ISO (International Organization for Standardization)-
certified, adhering to a different and perhaps more stringent set of criteria in their com-
pliance. Defining quality as just compliance was somewhat shortsighted, however,
as it limited quality’s contribution to the overall business and focused on external
agencies and organizations to ensure internal quality. Today quality has become inter-
nally defined and driven and has taken on a notion of a culture that is understood and
upheld by every employee, while retaining full compliance with accrediting, registering
and licensing agencies. The quality emphasis now extends to efficiencies in operations,
with quality staff providing input into business decisions where appropriate. This has
not changed the requirement for independence of the quality unit, but provides for
the appropriate involvement of quality input early on in process design and critical
business practices. These additional roles have increased the likelihood of positive
results for organizations. Figure 2.1 depicts the evolution of quality as a hierarchy.
Delighted customers
World
Delighted employees
Class
Strategic Planning
Efficient
Quality
Employee involvement
Quality
Reduced costs
Management
Less waste/rework
Quality
Compliance Assurance Effective
Quality
Sampling/testing Control
FIGURE 2.1 Quality hierarchy.
Transfusion Medicine and Hemostasis. http://dx.doi.org/10.1016/B978-0-12-397164-7.00002-1
Copyright © 2013 Elsevier Inc. All rights reserved. 11
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Eva D. Quinley, MS, SBB, CQA (ASQ)
Basic Principles: Quality is defined in many ways. The Webster Dictionary defines
quality as a distinguishing attribute, implying that it could be good or bad or just mediocre.
In transfusion medicine, quality of products and services must be as high as possible, and
such a definition requires that the quality of the processes by which those products and ser-
vices are manufactured and delivered must be as high as possible. The safety of donors and
patients is dependent upon such actions and decisions, which are made every day. A quality
definition that incorporates the evolving nature of the field of quality is sometimes used
by this author: ‘Quality is doing the right things right while utilizing the least resources
possible.’ In other words, quality is doing things correctly each and every time in the most
efficient way possible. This definition allows quality to include effectiveness and efficiency.
Quality control (QC) is a relatively narrow term, including activities such as sam-
pling and testing, that provides information about the quality of a product and can
provide assurance that something or someone is functioning at a given time as it is
supposed to function. QC is performed on reagents, equipment, and products; QC
also includes annual competency assessments of employees. QC activities may include
reviews of documentation for accuracy and completeness, visual inspections, and
measurements of product attributes. It is important to note that QC activities may be
performed by operation staff, by quality staff, or by both.
Quality assurance is a broader term, including all activities to ensure that processes
are developed and implemented as they are designed and assures that they achieve the
anticipated results. A quality assurance program is far reaching and includes activities
such as QC testing, development of standard operating procedures, deviation manage-
ment, validation, training and internal auditing. Traditionally, these activities are under
the realm of the quality department and are associated with the implementation of
robust quality systems. The goal of a good quality assurance program is to ensure con-
sistency in high quality output and to decrease errors. It is important to highlight that
the quality department is the champion of quality in an organization, and that quality
is everyone’s responsibility individually and collectively. This allows a quality culture to
emerge which then provides enhanced ‘quality’ in all areas with concomitant enhance-
ment in operational efficiencies, thus leading to cost reductions and improvements.
Quality Management Systems: Blood banks and transfusion services should
have an organized quality management system. A quality management system is a series
of processes that are linked together and controlled centrally to increase assurance of
product and manufacturing process quality. As part of the quality management sys-
tem, blood banks and transfusion services should have a quality policy describing their
overall intentions and direction with respect to quality. They should also have a quality
manual which details the various processes in the quality management system and how
the organization achieves success in implementing quality throughout its operations.
The number of elements in a quality system and the way they are grouped together
varies depending upon the organization.
AABB: AABB has organized its quality management system around ten Quality System
Essentials (QSEs) as found within the AABB Standards for Blood Banks and Transfu-
sion Services, 27th edition (Table 2.1). AABB assesses compliance with its Standards and
accredits blood banks and transfusion services. This accreditation is voluntary on the
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Quality Principles in Transfusion Medicine
TABLE 2.1 AABB Quality System Essentials
Organization Documents and Records
Resources Deviations
Equipment Assessments: Internal and External
Supplier and Customer Issues Process Improvement Through Corrective and Preventive Action
Process Control Facilities and Safety
part of the blood bank or transfusion service. Nonconformances or deficiencies in meet-
ing the Standards, which are found during an AABB assessment, are issued and correc-
tion is required for continued accreditation. A brief overview of each of the QSEs follows.
Organization: This QSE is intended to ensure that blood banks and transfusion
services have an organizational structure in place which is well defined and assures
that quality management is implemented and working throughout the organization,
including in the administrative, medical, technical and quality areas. It is leadership’s
responsibility to ensure that the organization is compliant and safe, not only for donors
and patients, but also for employees.
Regular reviews of the quality management system by leadership are an impor-
tant element of this QSE. Reports on activities within the quality management sys-
tem provide evidence as to whether the quality management system is effective or not.
Such reports may include quality indicators that apply to both quality and operational
areas. For example, a discarded product is both a quality and operational issue, as is
a customer complaint; monitoring these occurrences over a period of time may lead
to opportunities for quality improvements and increased operational efficiencies.
Reviewing reports and discussing issues regularly can lead to valuable insights and help
identify areas where process improvement is needed.
The quality organization must have authority and responsibility for the quality
management system, and there must be a process for individuals to communicate
quality concerns anonymously. Most facilities accomplish this through an anony-
mous ‘hotline’ where callers can report quality issues without fear of retribution.
Resources: This QSE relates to staff, requiring well-written job descriptions with job
qualifications that are clearly defined. It also addresses the need for staff to have orienta-
tion training, which includes information about the company and how it operates, and
training in job-related/specific tasks as well as in quality and safety. Additionally, staff
should be evaluated regularly and provided opportunity for continuing education. This
QSE is essential to successful quality operations.
Equipment: Equipment that is used in the blood banks and transfusion services must be
identified and qualified for its intended use. If applicable, equipment should be calibrated
against known standards on a routine basis according to written procedures. Equipment
should be on a documented schedule for maintenance, including cleaning. If repaired,
the equipment should be re-qualified prior to use. Equipment that is in disrepair or fails
QC should be removed from service and clearly marked to prevent its unintentional use.
There should be an investigation of the cause of any equipment failures.