Introduction/Background
The hemostatic system consisting of platelets, procoagulant and anticoagulant, and fibrinolytic and antifibrinolytic activities plays a key role in the maintenance of human viability. It achieves hemostatic balance by controlling bleeding without inducing pathologic thrombotic events. Until recently, the efficacy and safety of substitution of blood products have rarely been assessed with the use of state-of-the-art methodologies such as randomized trials. In a variety of cases, surrogate endpoints hinting toward clinical benefit (e.g., laboratory test results) have been used, but, in general, clinically important outcome measures (e.g., reduction in morbidity and mortality rates) have not been studied. Although it is generally agreed that platelet transfusions provide hemostasis in thrombocytopenic patients, this agreement is also the main reason why virtually no data supporting the efficacy and safety of the currently established practices are available.
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Platelet Transfusions
The recommended dosing for platelet transfusion is usually 0.5 × 10 11 platelets/10 kg body weight, which is the average platelet content of one single unit of whole blood (0.45 to 0.85 × 10 11 ). The therapeutic platelet dosage ranges from 2 to 4 × 10 11 platelets, which results in a post-transfusion platelet increment of 30,000/mcL in a patient, based on an average body weight of 70 kg. This therapeutic result can be achieved in the following three ways.
Platelet-Rich Plasma Preparation (United States)
In a validated process, one unit of whole blood is centrifuged. In the first step, a soft spin is used to obtain the platelet-rich plasma, followed by a hard spin to achieve sedimentation of the platelets. Sedimented platelets are then allowed to disaggregate and are resuspended in 50 to 60 mL plasma or another suspension medium (recovered platelets). The minimum content of this preparation is 0.45 × 10 11 /unit (U) platelets.
Buffy Coat Pool Preparation
The buffy coat layers (i.e., platelets with leukocytes) of whole blood are prepared in a validated process by means of specific-gravity centrifugation. In the second step, 4 to 6 buffy coats are pooled, recentrifuged by soft spin to obtain platelet rich plasma, and then recentrifuged by hard spin to obtain a platelet pellet. The platelet pellet is then disaggregated and resuspended in greater than 40 mL/0.5 × 10 11 platelets in plasma or nutrient solution. The minimum content of this preparation is 2.5 × 10 11 /U platelets.
Single-Donor Apheresis Preparation
This blood component is obtained by platelet apheresis of a single donor with the use of automated cell separation equipment. Depending on the donor and on the machine used, the platelet yield per procedure varies from 2 to 8 × 10 11 /U in a volume of greater than 40 mL/0.5 × 10 11 platelets.
Platelet buffy coat pool preparations and single donor apheresis preparations are therapeutically equivalent because only patients with alloimmunization need human platelet antigen/human leukocyte antigen (HPA/HLA)–typed preparations from single donors. The significance of the exposing the recipient to a greater number of pool donors is currently under investigation.
Products for Plasma Substitution
Fresh-frozen plasma (FFP) contains a physiologic range of all the clotting factors, fibrinogen (400 to 900 mg/U), plasma proteins (particularly albumin), electrolytes, physiologic anticoagulants (i.e., protein C, protein S, antithrombin, and tissue factor pathway inhibitor), and added anticoagulants. Because of processing and storage, FFP contains 15% to 20% less factor VIII levels compared with normal plasma. The shelf life is 1 year when stored at −18° C or lower. FFP is used as single unit quarantine plasma, pooled solvent/detergent-treated plasma, and single unit methylene blue–treated plasma. Photochemically treated FFP and solvent detergent FFP are approved methods of inactivating pathogens. However, both methods cause loss of clotting factors, particularly loss of factor VIII. Some solvent/detergent FFP preparations have reduced activity of protein S and alpha2-antiplasmin and have been associated with thromboembolic complications.
After thawing, the activity of labile clotting factors such as factor V and factor VIII decline gradually; 5 days after thawing, the activity of factor VIII has dropped by more than 50%, and the activities of factor V and factor VII have dropped to about 20% of their initial levels. Therefore it is recommended that FFP be used within 24 hours after thawing.
Evidence
In perioperative and intensive care medicine, the administration of blood, blood products, and substances influencing the coagulation system is guided by individualized hemotherapy regimens. The regimens are essential therapeutic interventions and frequently have to be shared among other specialties. Issues include:
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Lack of evidence and standardized guidelines for use of blood products and some plasma derivatives and pharmacologic agents
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Lack of accurate and rapid laboratory tools for evaluating the actual status and competence of the hemostatic system
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Individual variations caused by specific pathologic conditions or anatomic disruption
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Difficulties in assessing continued bleeding and the variable impact of pretreatment with anticoagulants or antiplatelet drugs
Bleeding is multifactorial and sometimes a dramatic event that is encountered in a multitude of clinical scenarios. However, the number of adequately designed and conducted clinical studies are limited. These limited data do not allow the generation of a broadly accepted treatment algorithm that is also applicable to therapeutic use of stable (plasmatic) and nonstable (cellular) blood products. In addition, manufacturers not only are not interested but also simply do not have the necessary resources to finance and conduct the necessary clinical studies. Therefore any recommendations for the use of platelets and FFP will have to be based on limited evidence only.
Platelets are intimately involved in hemostasis and thrombosis and interact with endothelial and white blood cells. Activated platelets themselves produce both immunomodulatory and proinflammatory mediators that, in turn, affect circulating cells and the endothelium. Treatment with platelet concentrates was introduced in the late 1950s for control and prevention of thrombocytopenic hemorrhaging in an effort to reduce bleeding-associated mortality in patients with acute leukemia. Since then, platelet transfusions have been predominantly used in hemato-oncologic patients in the context of bone marrow transplantation and chemotherapy.
Thrombocytopenia and severe active bleeding are widely accepted indications for therapeutic platelet transfusion (World Health Organization [WHO] grades 2 to 4) ( Table 23-1 ). However, because of the increasing number of complex surgeries and the widespread application of platelet inhibitors today, a large percentage of platelet transfusions are used in the treatment of surgical and intensive care unit (ICU) patients, especially in the settings of cardiac and vascular surgery, postpartum hemorrhaging, and liver transplantation.
| Bleeding Grade | Description of Bleeding |
|---|---|
| 0 | None |
| 1 | Petechial |
| 2 | Mild blood loss (no RBC transfusion required) |
| 3 | Gross blood loss (RBC transfusion required) |
| 4 | Debilitating blood loss |
* A minor hemorrhage is defined as a score of 1. A major hemorrhage is defined as a score of 2 or greater.
Nonetheless, platelet transfusions, in addition to their hemostatic function, can cause severe and potentially fatal adverse reactions such as transfusion reactions, thrombosis, inflammatory reactions, alloimmunization, refractoriness, and transfusion-related acute lung injury (TRALI). Because of these well-known adverse side effects, the concept of prophylactic transfusion based on the patient’s disease and the perceived bleeding risk should be challenged because it may put the patient at unnecessary risk and may do more harm. Therefore transfusion therapy should be restricted to patients with relevant bleeding problems.
The effectiveness of platelet preparations and FFP (i.e., plasma fractionation products) should be discussed in the context of a cell–cell surface–based model of coagulation. A dynamic balance exists between a cascade of activated proenzymes and factors influencing platelets’ procoagulatory and endothelial anticoagulatory functions. This balance might be challenged by underlying disease, concomitant medications, blood exposure to foreign surfaces (e.g., plastic tubing of cardiopulmonary bypass), and surgical stress. In addition, it has been demonstrated that storage significantly reduces platelets’ ability to respond adequately, leading to a loss of their hemostatic potential.
Monitoring
In general, immediate therapeutic interventions in hemostasis have to be performed without accurate laboratory tools. Standard laboratory tests such as platelet count, prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), and fibrinogen level represent only a small part of the entire coagulation process and, as such, are not able to reflect the rather complex interrelationships in hemostasis in vivo. Conventional coagulation tests by themselves do not convey any information about clot stability over time, nor do these tests give any information about fibrinolysis. Therefore these tests must be regarded as poor predictors of bleeding complications and, consequently, are only of limited use in the detection and monitoring of perioperative coagulation disorders ; however, a combination of aggregometric and viscoelastic methods may yield a broader diagnostic spectrum. In addition, point-of-care (POC) techniques are a valuable means of testing various aspects of hemostasis rapidly and can, at least partly, compensate for the methodologic limitations and diagnostic shortfalls of conventional coagulation testing. However, no single POC technique can provide adequate information about all aspects of the complex process of blood clotting (i.e., primary hemostasis, thrombin generation, clot formation/stabilization, and fibrinolysis).
Significant improvements in rotational thromboelastometric-measured variables were observed after platelet transfusion. This supports the evidence that platelets are, indeed, functional immediately after transfusion. In addition, in other studies comparing conventional techniques of determining platelet function such as bleeding time or light transmission aggregometry with three POC devices (i.e., Multiplate, Platelet Function Analyzer-100, and VerifyNow), the treatment effects of aspirin or clopidogrel were reliably assessed; it was found that VerifyNow had the highest effect size when the effects of aspirin were studied, and Multiplate showed the highest effect size when clopidogrel was compared with placebo. In the clinical setting, the implementation of hemostatic treatment algorithms with viscoelastic tests (thrombelastograms) reduced both the rate of transfusion of allogeneic blood products and the total cost of treatment for blood loss and coagulopathies in the majority of studies. However, whether POC testing is beneficial as a diagnostic tool for reducing perioperative morbidity and mortality has not been able to be demonstrated as of yet.
Platelet Transfusion
It is undisputed that patients with severe thrombocytopenia are at an increased risk of developing bleeding complications. Prevention and elimination of bleeding are therefore the main indications for platelet transfusion given either prophylactically to reduce the risk of bleeding or at the time when bleeding is actually occurring to stop the bleeding. Nevertheless, the optimal use of platelet transfusion remains unclear. Therefore severe thrombocytopenia in connection with clinically relevant bleeding is currently the only confirmed indication for transfusion of platelets; platelet counts are not a confirmed indication. All other indications should be considered relative indications that depend on the clinical circumstances of the individual patient. Furthermore, platelet function is dependent on storage time, the preparation method, and the patient’s underlying disease and comorbidities.
Variability and Overuse
Platelet transfusions and the use of FFP are only one factor in the prevention and treatment of perisurgical bleedings and major blood loss. Because no reliable cutoff values or guidelines are available, the variability between clinical centers in the number of platelets administered and in the percentage of patients transfused is significant. This significant variability has a geographic dependency, differs by the academic status and size of the hospital, and cannot be explained solely by medical reasons. It is a clinically well-accepted assumption that inadequate transfusion is associated with poor outcomes, but overtransfusion exposes the recipient to unnecessary risks such as sepsis, transfusion overloading, and infusion of variable amounts of some biologic response modifiers (BRMs). Because of the lack of demonstrated benefit and the limited availability of transfusion products due to demographic ageing and increased economic burden, the widespread overuse of platelet and plasma preparations must be stopped. In addition, the risk–benefit ratio of platelet and plasma transfusions should be re-evaluated on the basis of reliable facts so that donors and recipients are protected.
Risks of Platelet Transfusion
Platelet Transfusion Reaction
Reactions after transfusion of platelets, such as febrile nonhemolytic reactions, allergic reactions, transfusion-associated sepsis, or TRALI, are more frequently observed than transfusion reactions after transfusion with red blood cells and vary with storage time (bacteremia), leukodepletion, ABO matching, and the amount of supernatant depletion after storage. Bacterial sepsis associated with platelet transfusion today is the most frequent infectious complication (1 : 2000 to 1 : 3000) encountered in transfusion medicine and carries a mortality risk of 1 : 20,000 to 1 : 85,000. Storage of platelet products induces time-dependent changes in the product and the accumulation of biologically active, supernatant-soluble mediators and microparticles. It is hypothesized that these mediators play a direct role in the inflammatory and prothrombotic properties of platelet transfusions. In addition to other mechanisms, platelet are also recognized as the main source of circulating soluble CD40 (sCD40) ligands, which are part of the tumor necrosis factor family of cytokines. Platelet-derived sCD40 ligands not only play a significant role in the coagulation system but also are involved in the activation of neutrophils, which is one of the mechanisms of development of TRALI, the leading cause of transfusion-related fatalities (two-hit TRALI model).
Febrile nonhemolytic reactions are most common, and prestorage leukoreduction alone does not completely prevent febrile nonhemolytic reactions. Prestorage leukodepletion reduces the risk to 14% or even to 1% when platelet transfusions are ABO identical. Still, high concentrations of leukocyte- and platelet-derived bioactive substances can be found in stored platelet concentrates; thus a further reduction of nonfebrile nonhemolytic reactions to less than 1% can be achieved by washing with saline. Because platelet washing significantly increases platelet activation and decreases platelet aggregability, washed platelets should be reserved for patients with a history of severe allergic or anaphylactic transfusion reactions.
Platelet Transfusion
Alloimmunization and Refractoriness.
Platelet refractoriness is defined as a corrected count increment (CCI) of less than 7500 within 1 hour and less than 4500 within 20 hours after two transfusions of ABO-compatible fresh platelet concentrates (less than 3 days).
CCI = [ ( Post-transfusion count ) − ( pretransfusion count ) × body surface area in m 2 ] / number of platelets transfused ( in 10 11 )
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