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Fresh Frozen Plasma (FFP) is defined as the fluid portion of one unit of human blood that has been centrifuged, separated, and frozen solid at -18° C (or colder) within 6 hours of collection. Other single-donor plasma units, either frozen or liquid, may be substituted for FFP. Indications for these products are interchangeable with those for FFP except for coagulation factor V deficiency. For that reason, the term FFP in this statement otherwise applies to all single-donor plasma units. The use of plasma and its products has evolved over a period of four decades. The use of FFP has increased tenfold within the past 10 years and reached almost 2 million units annually. This trend may be attributable to multiple factors, possibly including decreased availability of whole blood due to widespread acceptance of the concept of component therapy. FFP contains the labile as well as the stable components of the coagulation, fibrinolytic, and complement systems; the proteins that maintain oncotic pressure and modulate immunity; and other proteins that have diverse activities. In addition, fats, carbohydrates, and minerals are present in concentrations similar to those in circulation. Although well-defined indications exist for the use of FFP in single or multiple coagulation deficiencies, indications for many of its other uses may be empiric.
In an effort to resolve some of the questions surrounding the steadily increasing use of FFP, the National Heart, Lung, and Blood Institute, the Center for Drugs and Biologics of the Food and Drug Administration, and the Office of Medical Applications of Research convened a Consensus Development Conference on FFP on September 24-26, 1984. After a day and a half of presentations by experts in the field, a consensus panel drawn from the medical professions, blood banking organizations, and the general public considered the evidence and agreed on answers to the following key questions:
What are the currently recommended clinical indications for FFP?
What are the risks of FFP?
What alternative therapies exist?
What is the current scientific knowledge regarding the effectiveness of FFP?
What directions for future research are indicated?
The administration of FFP has increased dramatically in recent years despite the paucity of definitive indications for its use. This increase has occurred in the presence of mounting evidence of its potential risks, which include viral hepatitis and possibly AIDS. Many patients who receive FFP can be managed more effectively and safely with alternative modalities. Appropriate use of FFP must be justified on clinical grounds until better evidence is available. Research to develop safer FFP and alternative therapies is encouraged.
There is no justification for the use of FFP as a volume expander or as a nutritional source. Safer alternative therapies exists.
FFP is indicated for some documented coagulation protein deficiencies as well as for selected patients who require massive transfusions. It is indicated for patients with multiple coagulation defects as in liver disease, in conjunction with therapeutic plasma exchange for thrombotic thrombocytopenic purpura, for infants with protein-losing enteropathy, and for selected patients with other immune deficiencies. Its use in most other cases should be discouraged.
Innovative educational efforts are needed to encourage appropriate use.
Few specific indications for the use of FFP exist. These indications generally are limited to the treatment of deficiencies of coagulation proteins for which specific factor concentrates are unavailable or undesirable. In addition, circumstances exist in which FFP has been employed and is believed to be of therapeutic value, but data supporting its efficacy are limited or unavailable (e.g., multiple coagulation protein deficiencies in the uncontrollably bleeding patient). Because such patients are often critically ill and satisfactory alternative therapy may not be at hand, FFP may be appropriate.
Indications for the use of FFP include the following:
FFP is efficacious for treatment of deficiencies of factors II, V, VII, IX, X, and XI when specific component therapy is neither available nor appropriate. Requirements for FFP vary with the specific factor being replaced. For example, hemostatic levels of factor IX in a patient with severe deficiency are difficult to achieve with FFP alone, whereas patients with severe factor X deficiency require factor levels of about 10 percent to achieve hemostasis and are easily treated with FFP.
Patients who are anticoagulated with warfarin are deficient in the functional vitamin K dependent coagulation factors II, VII, IX, and X, as well as proteins C and S. These functional deficiencies can be reversed by the administration of vitamin K. However, for anticoagulated patients who are actively bleeding or who require emergency surgery, FFDP (or single-donor plasma) can be used to achieve immediate hemostasis.
Use of FFP in massive blood transfusion, for which there is less credible evidence of efficacy, appears to have increased in frequency in the past decade, possibly due in part to the relative unavailability of whole blood. Pathological hemorrhage in the massively transfused patient is caused more frequently by thrombocytopenia than by depletion of coagulation factors. The empiric use of FFP to reverse hemostatic disorders should be confined to those patients in whom factor deficiencies are presumed to be the sole or principal derangement. There is no evidence that the prophylactic administration of FFP decreases transfusion requirements in multiply transfused patients who do not have documented coagulation defects.
FFP can be used as a source of antithrombin III in patients who are deficient in this inhibitor and are undergoing surgery or who require heparin for treatment of thrombosis.
FFP is useful in infants with secondary immunodeficiency associated with severe protein-losing enteropathy and in whom total parenteral nutrition is ineffectual. FFP also can be used as a source of immunoglobulin for children and adults with humoral immunodeficiency. However, the development of a purified immune globulin for intravenous use largely has replaced FFP.
FFP may be beneficial for the treatment of thrombotic thrombocytopenic
purpura.
The risks of FFP include disease transmission, anaphylactoid reactions,
alloimmunization, and excessive intravascular volume. The potential viral
infectivity of FFP probably is similar to that of whole blood and red blood
cells. The rate of posttransfusion hepatitis--predominantly non A, non B-depends
on many factors, including donor selection. The incidence of nonicteric and
icteric hepatitis following multiple transfusions probably ranges between 3 and
10 percent. In rare instances, acquired immunodeficiency syndrome (AIDS) is
transmitted by blood transfusions and possibly by FFP. Allergic or anaphylactoid
reactions can occur in response to FFP administration and may vary from hives to
fatal noncardiac pulmonary edema. The potential for alloimmunization is present,
as demonstrated by the infrequent formation of Rh antibodies. As with any
intravenously administered fluid, excessive amounts of FFP may result in
hypervolemia and cardiac failure.
Evidence indicates that other plasma components (e.g., single-donor plasma) that do not meet the criteria of FFP may have adequate levels of coagulation factors and are suitable for patients in whom FFP is indicated. Single-donor plasma is efficacious in the treatment of mild deficiencies of stable clotting factors. It also is of value in treatment of multiple deficiencies as in reversal of warfarin effects or in liver disease.
Safe and effective alternative treatment often exists so that FFP is no longer the therapy of choice in many conditions. Cryoprecipitate should be used when fibrinogen or von Willebrand factor is needed. For treatment of hemophilia A, cryoprecipitate or factor VIII concentrates, heated or unheated, are available. For treatment of severe hemophilia B, factor IX complex is preferable. Both of these concentrates are prepared from pooled plasma, and the risk of virus transmission is high. The factor IX concentrate carries the additional hazard of thrombogenicity.
Crystalloid, colloid solutions containing albumin or plasma protein fraction, hydroxyethyl starch, and dextran are preferable to FFP for volume replacement. The practice of administering both packed red cells and FFP to the same patient should be discouraged, as this adds to the cost and doubles the infection rate. When conditions are appropriate, whole blood should be given.
For nutritional support, amino acid solutions and dextrose are available.
The most important alternative to the use of FFP is a comprehensive program of blood conservation. This includes measures such as autologous donation before elective surgery, the infusion of shed blood, and the realization that in many patients normovolemic anemia is not an indication for transfusion.
Because of the special nature of neonatal requirements for blood and blood
products, these issues were not addressed specifically in this report.
Nonetheless, efforts should be exerted to continue to avoid undue exposure to
multiple donor sources.
There is little scientific evidence to support the increasing use of FFP in
clinical medicine. While FFP is a reliable solution for intravascular volume
replacement in acute blood loss, alternative therapies are equally satisfactory
and considerably safer. There is no documentation that FFP has a beneficial
effect when used as part of the transfusion management of patients with massive
hemorrhage. FFP contains the major plasma proteins, including the labile
coagulation factors (V and VIII), but in clinical practice other blood
components or derivatives usually provide greater efficacy.
Research aims should be directed toward:*
A national prospective study to identify the current patterns of use of FFP and related products.
Better understanding of the balance between coagulation and fibrinolytic systems, their activators and inhibitors, and their roles in the coagulopathies associated with liver disease and massive transfusion.
Definition of the etiology of uncontrollable hemorrhage in the massively transfused patient.
Clinical investigations to identify the factor(s) in FFP that appears to cause beneficial effects in patients who are undergoing apheresis for treatment of syndromes such as thrombotic thrombocytopenic purpura.
Blood and plasma salvage during operative procedures.
Production of the safest possible specific plasma constituents and substitutes.
Processes or methods to eliminate or inactivate viral and bacterial contaminants.
Technology involving membrane-separation techniques to separate cellular products more effectively.
Development of an efficient system by which a larger volume of FFP can be collected from a single donation thus lessening the number of donor exposures in single recipients.
The use of FFP is controlled locally and determined largely by existing
practice. Attempts to alter FFP use frequently have been ineffective. The most
successful attempts can be attributed to a strong local proponent of modern
transfusion practices. Ongoing collaborative efforts, including component
therapy workshops involving clinicians and blood bank directors, can do much to
alter existing practices. Increased attention to the risks and benefits of
component therapy in the medical schools and teaching hospitals also may change
the use of FFP. When appropriate, information regarding potential risks and
benefits of FFP and other blood products should be made available to patients
who receive those products.
James L. Tullis, M.D.
Panel Chairman
Professor of Medicine Emeritus
Harvard University Medical School
New England Deaconess Hospital
Boston, Massachusetts
Barbara Alving, M.D.
Chief, Coagulation Laboratory
Walter Reed Army Institute of Research
Associate Professor of Medicine
Uniformed Services University of the Health Sciences
Washington, D.C.
Joseph R. Bove, M.D.
Professor of Laboratory Medicine
Yale University School of Medicine
New Haven, Connecticut
Charles J. Carman
Board of Directors
The National Hemophilia Foundation
Stow, Ohio
Ralph B. D'Agostino, Ph.D.
Professor of Mathematics and Statistics
Boston University
Boston, Massachusetts
Jessica H. Lewis, M.D.
Professor of Medicine
University of Pittsburgh School of Medicine
Vice President, Research/Coagulation
Central Blood Bank of Pittsburgh
Pittsburgh, Pennsylvania
Ronald D. Miller, M.D.
Professor and Chairman of Anesthesia
Professor of Pharmacology
University of California School of Medicine
San Francisco, California
William W. Monafo, Jr., M.D.
Professor of Surgery
Washington University School of Medicine
Director, Barnes Hospital Burn Center
St. Louis, Missouri
Bruce A. Reitz, M.D.
Cardiac Surgeon-in-Charge
Johns Hopkins Hospital
Professor of Surgery
Johns Hopkins University School of Medicine
Baltimore, Maryland
J. Gordon Scannell, M.D.
Clinical Professor of Surgery
Harvard Medical School
Massachusetts General Hospital
Boston, Massachusetts
The Rev. Sydney Wilde-Nugent, MT(ASCP)SBB, MDiv
Associate Minister
Cedar Lane Unitarian Church
Bethesda, Maryland
James Allen, M.D.
"Epidemiology of AIDS in the United States: Cases Associated with Transfusions"
Chief, Surveillance Section
Centers for Disease Control
Atlanta, Georgia
Robert H. Bower, M.D.
"Fresh Frozen Plasma as a Nutritional Supplement"
Director
Nutritional Support Service
Assistant Professor of Surgery
University of Cincinnati
Cincinnati, Ohio
Delos M. Cosgrove, M.D.
"Postcardiac Pulmonary Bypass"
Staff Surgeon
Department of Thoracic and Cardiovascular Surgery
The Cleveland Clinic Foundation
Cleveland, Ohio
Richard B. Counts, M.D.
"Modified Whole Blood and Cryoprecipitate"
Managing Director
Puget Sound Blood Center
Associate Professor of Medicine
University of Washington
Seattle, Washington
Robert H. Demling, M.D.
"Clinical Significance of Decreased Oncotic Pressure"
Associate Professor of Surgery Harvard Medical School
Boston, Massachusetts
Daniel Deykin, M.D.
"Coagulopathy of Acquired Factor Deficiency in Liver Disease and Deranged Hemostasis of Uremia"
Chief, Medical Service
Boston Veterans Administration Medical Center
Boston, Massachusetts
John S. Finlayson, Ph.D.
"Immune Globulin"
Director, Plasma Proteins Branch
Center for Drugs and Biologics
Food and Drug Administration
Bethesda, Maryland
George Grady, M.D.
"Risk of Disease Transmission"
Director, State Laboratory Institute
Massachusetts Department of Public Health
Professor of Medicine
Tufts University School of Medicine
Boston, Massachusetts
John H. Griffin, Ph.D.
"Physiology of Clotting Factors"
Associate Member
Scripps Clinic and Research Foundation
La Jolla, California
David M. Heimbach, M.D.
"Hemostasis in Massively Transfused Trauma Patients"
Professor of Surgery
University of Washington
Director, Burn Unit
Harbor View Medical Center
Seattle, Washington
Bernard Horowitz, Ph.D.
"Plasma Fractions as Alternative to Fresh Frozen Plasma"
Director of Research and Development
Blood Derivatives Program
New York Blood Center, Inc.
New York, New York
Gerald S. Moss, M.D.
"Salt and Water Versus Protein-Containing Solutions"
Chairman
Department of Surgery
Michael Reese Hospital and Medical Center
Chicago, Illinois
Thomas M. Saba, Ph.D.
"Plasma Fibronectin: Its Potential Therapeutic Value"
Professor and Chairman
Department of Physiology
Albany Medical College of Union University
Albany, New York
William C. Shoemaker, M.D.
"Evaluation of Fresh Frozen Plasma, Plasma Protein Fraction, Albumin, Whole Blood, and Crystalloids"
Professor of Surgery
Department of Surgery
University of California, Los Angeles School of Medicine
Harbor-UCLA Medical Center
Torrance, California
Scott N. Swisher, M.D.
"Overview of Fresh Frozen Plasma"
Professor of Medicine
College of Human Medicine
Michigan State University
East Lansing, Michigan
Stan Urbaniak, B.Sc., M.B.Ch.B., Ph.D., F.R.C.P.E.
"Coagulopathy of Apheresis or Exchange"
Regional Director North-East Scotland Blood Transfusion Service
Royal Infirmary
Foresterhill, Aberdeen SCOTLAND
Dennis M. Donohue, M.D. (Cochairman)
Assistant to the Director
Center for Drugs and Biologics
Food and Drug Administration
Bethesda, Maryland
George Nemo, Ph.D. (Cochairman)
Chief, Blood Resources Branch
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
National Institutes of Health
Bethesda, Maryland
Michael J. Bernstein
Director of Communications
Office of Medical Applications of Research
National Institutes of Health
Bethesda, Maryland
Susan Clark
Social Science Analyst
Office of Medical Applications of Research
National Institutes of Health
Bethesda, Maryland
Richard B. Counts, M.D.
Managing Director
Puget Sound Blood Center
Associate Professor of Medicine
University of Washington
Seattle, Washington
Carol M. Florance
Information Specialist
Public Inquiries and Reports Branch
National Heart, Lung, and Blood Institute
National Institutes of Health
Bethesda, Maryland
Edward Lowenstein, M.D.
Professor of Anesthesia
Harvard Medical School
Anesthetist
Massachusetts General Hospital
Boston, Massachusetts
Charles E. Lucas, M.D.
Professor of Surgery
Wayne State University
Detroit, Michigan
Gerald S. Moss, M.D.
Chairman
Department of Surgery
Michael Reese Hospital and Medical Center
Professor of Surgery
Pritzker School of Medicine
University of Chicago
Chicago, Illinois
Ernest R. Simon, M.D.
Executive Vice President for Medical Affairs
Blood Systems, Inc.
Scottsdale, Arizona
James L. Tullis, M.D.
Professor of Medicine Emeritus
Harvard University Medical School
New England Deaconess Hospital
Boston, Massachusetts
National Heart, Lung, and Blood Institute
Claude Lenfant, M.D.
Director
Office of Medical Applications of Research, NIH
Itzhak Jacoby, Ph.D.
Acting Director
Center for Drugs and Biologics, FDA
Harry M. Meyer, M.D.
Director
Since the NIH Consensus Statement on Fresh Frozen Plasma: Indications and Risks was issued, additional information has become available that supplements the original statement.
Recommendations included in the statement continue to be valid. However, it should be noted that the current frequencies of infectious virus transmission by single units of blood or blood components are lower than reported in the statement. For more recent information, see Schreiber GB. The risk of transfusion-transmitted viral infections. NEJM 1996;334:1685-1690. Also, "non-A, non-B hepatitis" is now known to be almost exclusively caused by the hepatitis C virus (HCV). A test for HCV antibodies was developed several years ago, and a recently improved version is in universal use in the United States.
No priorities are implied in this sequence
