Optimizing platelet transfusion therapy☆
Introduction
Platelet transfusion is widely employed in modern tertiary care medical practice for prevention and treatment of thrombocytopenic bleeding in patients with hematologic malignancies, solid tumors, major surgical bleeding, trauma and, much less often, in patients with platelet dysfunction syndromes. About two million platelet transfusions are given per year in the United States alone. The cost of obtaining and making these platelets ready for transfusion probably exceeds one billion dollars annually. In the United States, approximately 75% of these transfusions are pheresis platelets, which require that a donor be recruited, leave work and spend an hour or two connected to a cell separator. Thus platelet transfusion represents a significant human resource and financial investment on the part of society and the health care system. Despite this major investment, there are virtually no clinical outcomes data derived from randomized trials demonstrating that platelet transfusion improves clinical outcome compared with no transfusions, or alternative strategies for managing hemostatic risks or bleeding. Most of the practices currently in use evolved during a period before modern regulatory and clinical trial standards existed. In addition to cost and efficacy issues, there is also a social utility concern. Recruiting new blood donors for pheresis platelets as contrasted with use of previous collected and tested whole blood collections represents increased risks for and drains on society's altruistic donors.
What makes these questions particularly compelling, in our opinion, is a growing body of data that raises questions about issues of safety. Various voluntary organizations in the USA (but not the Food and Drug Administration) have mandated testing of stored platelets for contaminating bacteria as of March, 2004. Thrombosis and multi-organ failure are newly described potential risks of platelet transfusion.[1], [2], [3] The immunologic effects of platelet transfusions, referred to as transfusion immunomodulation, have not been studied in contrast to red cell transfusions.
Many comprehensive reviews of platelet transfusion therapy have appeared in recent years, including official guidelines from the British Council for Standards in Haematology and the American Society of Oncology.[4], [5], [6] We will focus on issues of platelet transfusion therapy critically important to clinical outcomes and try to answer the question “what does the practicing clinician need to know for best results?” These topics include use of leukoreduced transfusions, the role of ABO identical transfusions, pheresis versus whole blood-derived platelet transfusions, prophylactic versus therapeutic use of platelet transfusions, the transfusion threshold for prophylactic transfusion in the non-bleeding patient and the threshold for prophylactic transfusions prior to invasive procedures. We also will address developing issues of scientific controversy that could radically alter the approach to platelet transfusion therapy in the near future. These include bacterial testing and pathogen inactivation of stored platelets, and the new hypothesis that platelet transfusions can cause thrombosis, multi-organ failure and adverse immunologic effects. We will not address issues such as storage effects, quality control or other important topics that are not directly relevant to therapeutic decisions.
Section snippets
Leukoreduction, ABO matching and platelet transfusion refractoriness
Leukoreduction of platelet transfusions, is in our opinion, the most important safety improvement since the advent of infectious disease testing. Non-leukoreduced platelet transfusions are associated with clinical complications such as febrile transfusions reactions (perhaps as many as 30–60% of patients),7 HLA alloimmunization and transfusion refractoriness (perhaps as many of 40–80% of repeatedly transfused patients in some settings)8 and CMV transmission (perhaps as many as 30% of patients).9
Prophylactic versus therapeutic platelet transfusions
Platelet transfusions are predominately administered to patients with few or no signs of clinical hemorrhage, the “prophylactic” approach. This derives from the clinical experience that patients with very low platelet counts (usually <10,000/μl) due to immune thrombocytopenia or myeloablative chemotherapy more frequently have bleeding than patients with higher or normal platelet counts.29 Similarly, clinical experience is that in most cases, thrombocytopenic bleeding responds to platelet
Transfusion thresholds for prophylactic platelet transfusions
The underlying clinical paradigm in hematology for three decades is that prophylactic transfusion is safer than waiting for bleeding manifestations before initiating platelet transfusions. Clinical anxiety derives primarily from the risk of devastating intracranial hemorrhage in thrombocytopenic patients. This extent of the risk of this dread and irreversible complication is unknown in the untransfused patient population. While uncommon, intracranial hemorrhage is not rare, with most
Transfusion thresholds for prophylactic platelet transfusions prior to surgery or invasive procedures
While there are abundant data on prophylactic transfusions in non-bleeding patients, there are fewer studies on the threshold that should be used to administer prophylactic platelet transfusions prior to surgery or invasive procedures. While the general recommendation has been that platelets should be given at counts <50,000/μl for such hemostatic challenges,34 there is very little or no data to support this commonly used threshold. Every clinician can remember patients who bled extensively
Single-donor pheresis versus random-donor whole blood-derived platelets
There is still much discussion about whether platelets should be given as a pool of whole blood-derived “random-donor platelets” or as pheresis platelets. Random-donor platelets are made as a by-product of whole blood collection either from platelet rich plasma as is done in US or by the buffy coat technique more commonly used in Europe. Pheresis platelets on the other hand are collected from single donors using cell separators.
In the late 1970s and early 1980s pheresis platelets were reserved
Transfusion reactions to platelets and the role of pheresis platelets
Febrile reactions from non-leukoreduced pheresis platelets were reported in 1990 to be nearly half that with random platelets (8.4% versus 14.2%) despite comparable levels of contaminating WBC. This reduction was proposed as an additional argument for the preferential use of pheresis products.58 In retrospect this result was probably due to pheresis platelets at that time being stored for a shorter time before transfusion.59 When bedside leukoreduction was introduced for red cells it markedly
Donor safety, cost and pheresis platelets
What is often completely overlooked in arguing for the use of pheresis platelets is the safety of the donor and the cost in time to both the donor and employer.80 Demands for whole blood continue to increase and will do so independent of platelet usage. Even though the risks for blood donors are small there is no alternative source for red cells. Pheresis carries some additional risks for the donor such as citrate toxicity, hemolysis, air embolism, hypovolemia and sustained decreases in
Bacterial contamination of platelet transfusions
In the last 10 years there has been a remarkable reduction in the risk of viral transmission following transfusion. As a result some complications, such as bacterial contamination, previously considered rare, have now become a higher priority. The use of sterile bags, and procedures to decontaminate the donor's venipuncture site are intended to produce sterile blood products but bacterial contamination from the collection site, or as a result of asymptomatic bacteremia in the donor still occur.
Pathogen inactivation
Pathogen inactivation is an exciting new paradigm for transfusion medicine. For the past 50 years the standard approach to blood safety has relied on a detailed donor history and the ability to detect specific antibodies that develop in a delayed fashion following viral exposure. Adding more and more intense questions to the screening process, increasing the sensitivity and the numbers of assays to cover new transmissible pathogens has allowed a steady reduction in the risk of transfusion.
Transfusion-related acute lung injury
TRALI (Transfusion-related acute lung injury) is a sometimes life threatening, often underdiagnosed complication of platelet transfusion thought to be due to infusion of plasma containing anti-granulocyte, anti-HLA or other antibodies, either with or without a second stimulus from bioactive substances that cause the non-cardiogenic pulmonary edema that characterizes the syndrome.[93], [94], [95] Pathogenesis appears to be more complex than mere infusion of anti-white cell antibodies, but the
Febrile and allergic reactions
The most common, and fortunately, least clinically severe, reactions that occur to leukoreduced platelet transfusions are symptoms of fever and rigors that are called febrile or inflammatory reactions, and symptoms of rash and urticaria that are called allergic or anaphylactoid reactions. Both febrile reactions and allergic reactions to leukoreduced transfusions can be largely abrogated by use of washed or plasma reduced platelet concentrates, although no randomized trials have been performed.
Hemolysis/volume overload
Administration of platelets almost invariably involves simultaneous administration of a quarter to half a liter of plasma, on a daily or every other day basis in the case of patients receiving myeloablative chemotherapy. Given the high titers of anti-A and anti-B present in some donor plasmas, use of ABO non-identical platelets is occasionally followed by moderate to severe hemolysis. Likewise, the administration of large amounts of plasma can cause symptoms of cardiac failure and volume
Immunomodulation/multi-organ failure
A growing body of data over the last two decades has demonstrated that blood transfusions have broadly immunomodulatory effects of clinical significance.11 These data are a source of substantial disagreement over interpretation. Transfusions of unmodified whole blood or red cells have been associated with beneficial effects on solid organ (but not marrow or stem cell) allograft rejection, repetitive spontaneous abortion and chronic inflammatory diseases such as Crohn's disease. Unfortunately
Transmission of viral infection
As mentioned in the section comparing pheresis and whole blood-derived platelets, the risk of transmission of known infectious agents by platelet transfusions is now very low and of minimal to unknown clinical importance. CMV transmission remains a concern, primarily in immunologically compromised patients. It is not clear whether the 1% infection rate seen in recipients of seronegative blood or leukoreduced blood represents nosocomial transmission, reactivation of infection in patients falsely
Alternatives to platelet transfusions
Currently there are no alternatives to platelet transfusion that have been unequivocally accepted as equally efficacious and safe. Amongst the alternatives that have or are being investigated are use of growth factors such as IL-11 or thrombopoietin, use of anti-fibrinolytics such as epsilon-amino caproic acid and soluble platelet membrane preparations. The single greatest advance in platelet transfusion therapy would be the development of effective therapies for malignant disease that did not
Practice Points
- •
The need for prophylactic platelet transfusions to non-bleeding patients has not been established in randomized trials. In doubtful situations, withholding transfusion is a reasonable course.
- •
For bleeding patients with platelet counts of <100,000/μl or documented platelet dysfunction, platelet transfusion is a reasonable alternative. Bleeding that does not respond to a single platelet transfusion is extremely unlikely to respond to multiple transfusions.
- •
For non-bleeding patients, a prophylactic
Research Agenda
- •
Whether or not prophylactic platelet transfusions are of benefit or actually harmful needs to be established in randomized trials.
- •
The threshold for prophylactic platelet transfusions in patients about to undergo surgery or invasive procedures remains to be determined by observational or randomized clinical trials.
- •
The appropriate methods and benefits of preventing bacterially contaminated platelet transfusions need to be determined.
- •
The safety and efficacy of pathogen inactivation technologies in
References (98)
- et al.
Prophylactic platelet transfusions: which dose is the best dose? A review of the literature
Transfus. Med. Rev.
(2003) - et al.
A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion-associated CMV infection after marrow transplant
Blood
(1995) Prevention of alloimmunization against platelets
Blood
(1991)Platelet transfusion therapy
Hematol. Oncol. Clin. North Am.
(1990)- et al.
Platelet prophylaxis in acute non-lymphoblastic leukaemia
Lancet
(1978) - et al.
Do basic laboratory tests or clinical observations predict bleeding in thrombocytopenic oncology patients?
Transfus. Med. Rev.
(2002) - et al.
Safety of stringent prophylactic platelet transfusion policy for patients with acute leukaemia
Lancet
(1991) - et al.
Bleeding due to thrombocytopenia in acute leukemias and reevaluation of the prophylactic platelet transfusion policy
Am. J. Med. Sci.
(1986) - et al.
Safety and cost effectiveness of a 10 × 10(9)/l trigger for prophylactic platelet transfusions compared with the traditional 20 × 10(9)/l trigger – a prospective comparative trial in 105 patients with acute myeloid leukemia
Blood
(1998) - et al.
A prospective randomized trial of prophylactic platelet transfusion and bleeding incidence in hematopoietic stem cell transplant recipients: 10,000/L versus 20,000/μL trigger
Biol Blood Marrow Transplant.
(2002)
Transjugular liver biopsy in patients with hematologic malignancy and severe thrombocytopenia
J. Vasc. Interv. Radiol.
Central venous catheter placement in patients with disorders of hemostasis
Chest
Hepatitis C virus transmission by a blood donation negative in nucleic acid amplification tests for viral RNA
Lancet
Delayed alloimmunization using random single donor platelet transfusions: a prospective study in thrombocytopenic patients with acute leukemia
Blood
Delayed alloimmunisation by random single donor platelet transfusions. A randomised study to compare single donor and multiple donor platelet transfusions in cancer patients with severe thrombocytopenia
Lancet
Considerations in the selection of a platelet component: apheresis versus whole blood-derived [Review]
Transfus. Med. Rev.
Pooled platelet concentrates: maybe not fancy, but fiscally sound and effective
Transfus. Sci.
Blood product-associated bacterial sepsis
Transfus. Med. Rev.
Bacterial contamination of platelet concentrates: incidence, significance, and prevention
Semin. Hematol.
The rationale for pathogen inactivation treatment of platelet components –introduction
Semin. Hematol.
Transfusion of pooled buffy coat platelet components prepared with photochemical pathogen inactivation treatment: the euroSPRITE trial
Blood
Transfusion-related acute lung injury [Review]
Transfus. Med. Rev.
Occurrence of allogeneic HLA and non-HLA antibodies after transfusion of prestorage filtered platelets and red blood cells: a prospective study
Blood
Aspirin and mortality from coronary bypass surgery
N. Engl. J. Med.
Thrombocytopenia in critically ill surgical patients: a case-control study evaluating attributable mortality and transfusion requirements
Crit. Care
Increased platelet transfusion requirement is associated with multiple organ dysfunctions in patients undergoing hematopoietic stem cell transplantation
Bone Marrow Transplant.
Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society of Clinical Oncology [Review]
J. Clin. Oncol.
The role of the plasma from platelet concentrates in transfusion reactions
N. Engl. J. Med.
The role of ABO matching in platelet transfusion
Eur. J. Haematol.
Cytomegalovirus immune globulin and seronegative blood products to prevent primary cytomegalovirus infection after marrow transplantation
N. Engl. J. Med.
Transfusion immunomodulation
Transfusion of ABO-mismatched platelets leads to early platelet refractoriness
Br. J. Haematol.
ABO and platelet transfusion revisited
Ann. Hematol.
A possible survival advantage in adults with acute leukemia receiving ABO-identical platelet transfusions
Am. J. Hematol.
ABO-mismatched platelet transfusions and clinical outcomes after cardiac surgery
Transfusion
The second century of ABO: and now for something completely different
Transfusion
Refractoriness to platelet transfusion
Curr. Opin. Hematol.
Leukodepleted-ABO-identical blood components in the treatment of hematologic malignancies: a cost analysis
Am. J. Hematol.
WBC reduction of RBC transfusions is associated with a decreased incidence of RBC alloimmunization
Transfusion
Selecting donors of platelets for refractory patients on the basis of HLA antibody specificity
Transfusion
Platelet crossmatching: a direct approach to the selection of platelet transfusions for the alloimmunized thrombocytopenic patient
Am. J. Clin. Pathol.
Circulating immune complexes involving the ABO system after platelet transfusion
Br. J. Haematol.
Platelets coated with ABO immune complexes from refractory patients are associated with increased adhesion to monocytes
Transfusion
Interaction of platelet fc and complement receptors with circulating immune complexes involving the AB0 system
Vox Sang.
Antibodies to plasma proteins: an association with platelet transfusion refractoriness
Br. J. Haematol.
Optimizing platelet transfusions in chronically thrombocytopenic patients
Semin. Hematol.
The prophylactic treatment of thrombocytopenic leukemic patients with platelets: a double blind study
Transfusion
Cited by (0)
- ☆
Financial Disclosure: Dr. Blumberg and Dr. Heal have received lecture honoraria, consultant fees and research funding in the past from Gambro BCT, Baxter/Fenwal, Ortho Biotech and Pall Biomedical.