Guidelines for blood component therapy

Red blood cell concentrates

Transfusion of red blood cells (RBCs) is one of the most common medical interventions performed in the United States, with over 11 million units of RBCs transfused annually. RBCs are typically packed (pRBCs) with a preservative solution that allows refrigerated storage for up to 42 days. Each unit has a hematocrit of approximately 60%, and transfusion of one unit of pRBCs is typically expected to result in a hemoglobin (Hgb) increase of 1 g/dL in an adult with stable blood volume. Despite previous published guidelines, there remains significant variation in the practice of transfusing patients. Whereas some clinicians base the decision to transfuse solely upon Hgb level, many guidelines maintain that transfusions should be given for overall clinical status, patient preference, and availability of alternative therapies. ^,

A recent systematic review and meta-analysis evaluating the efficacy of RBC transfusion included 31 randomized clinical trials (RCTs) with over 12,000 patients who were randomized to a higher Hgb concentration as the threshold for transfusion (referred to as liberal transfusion; Hgb <10 g/dL) or to a lower Hgb concentration (referred to as restrictive transfusion; Hgb <7–8 g/dL). Patients in the restrictive group were 43% less likely to receive an RBC transfusion than those in the liberal group. Overall, there was no difference in 30-day mortality between the two groups, and results were similar among trials with thresholds of 7 and 8 g/dL. Other outcomes did not differ significantly between restrictive and liberal transfusion groups, including infection (pneumonia, wound, bacteremia), myocardial infarction, and congestive heart failure.

With these data in mind, the AABB recommends a restrictive RBC transfusion threshold in which transfusion is not indicated until the Hgb falls below 7 g/dL for the majority of hemodynamically stable patients, including those who are critically ill. For patients undergoing orthopedic or cardiac surgery and those with cardiovascular disease, the AABB recommends a restrictive transfusion threshold with an Hgb goal of 8 g/dL. Although they do comment that the restrictive threshold of 7 g/dL is likely comparable with 8 g/dL, RCT evidence is not available for all patient categories. These recommendations do not apply to patients with acute coronary syndrome, severe thrombocytopenia, and chronic transfusion-dependent anemia, as the evidence is insufficient in these disease processes.

Platelet concentrates

Platelet concentrates can be prepared by apheresis or from whole blood using either the buffy-coat or platelet-rich plasma methods. Whereas apheresis platelets are obtained from one donor, the buffy-coat and platelet-rich plasma methods require pooling of platelets from several donors (usually four to six). Unlike other blood components, platelets are stored at 22°C with continuous agitation and have a shelf-life of up to 5–7 days out of concern for possible bacterial growth during storage.

Thrombocytopenia is correlated with increasing illness severity, sepsis, and organ dysfunction; however, the effect of thrombocytopenia on clinically significant spontaneous hemorrhage remains unclear. Platelet transfusion strategies are driven by the need to stop (therapeutic) or prevent (prophylactic) bleeding. Although an increased risk of bleeding has been demonstrated with a platelet count below 5 × 10 ⁹ /L and spontaneous hemorrhage rarely occurs above 10 × 10 ⁹ /L, there is a general lack of evidence to support specific platelet thresholds in most critical care and surgical settings.

In patients undergoing surgical or invasive procedures, relative factors that contribute to the decision to transfuse platelets perioperatively include the type of procedure, preoperative platelet counts, degree of active or anticipated hemorrhage, and presence of antiplatelet medications or disorders that affect platelet function. For major surgeries or invasive procedures that carry an inherently elevated risk of bleeding, the platelet count should be maintained at greater than 50 × 10 ⁹ /L. As a significant number of patients who undergo cardiac surgery experience platelet dysfunction related to cardiopulmonary bypass, hypothermia, hemodilution, and platelet activation, prophylactic platelet transfusion should not be performed unless the patient is on antiplatelet therapy. Postoperatively, platelets should be transfused in the setting of active bleeding with a platelet count less than 50 × 10 ⁹ /L with no obvious source of hemorrhage. For minor surgeries and minimally invasive procedures (central line placement, angiography, endoscopy, lumbar puncture, paracentesis), the platelet count should be maintained above 20–30 × 10 ⁹ /L. For neurosurgical procedures and other procedures that occur within a closed, defined space (including ocular procedures), a platelet count above 100 × 10 ⁹ /L is recommended.

Prophylactic platelet transfusions are recommended only for platelet counts below 10 × 10 ⁹ /L unless other factors that increase the risk of bleeding are present. In patients with qualitative defects in platelet function, platelet count is not a reliable indicator for transfusion, and transfusion decisions and monitoring of efficacy should be based on the setting and clinical features. In the setting of massive hemorrhage, the platelet count should be maintained above 50 × 10 ⁹ /L, and above 75 × 10 ⁹ /L with any associated injury to the central nervous system. The transfusion of platelet concentrates is not generally considered appropriate when thrombocytopenia is the result of immune-mediated destruction or in patients with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.

Fresh frozen plasma

Fresh frozen plasma (FFP) has a shelf-life of up to a year at −18°C but requires 30 minutes or more to thaw, limiting immediate availability. Once thawed, it has a 5-day shelf-life before it must be discarded. FFP is widely used, but there are limited specific indications for its use, and there is a dearth of evidence for its efficacy in many clinical settings. FFP is frequently used to correct an abnormal international normalized ratio (INR) in nonbleeding patients. In this setting, many patients have adequate coagulation function and transfusion is unnecessary. FFP may be appropriate in patients with a known coagulopathy who are bleeding or at risk of bleeding when a specific therapy or factor concentrate is not appropriate or is unavailable. This includes patients with a vitamin K deficiency or who require reversal of warfarin therapy. Additionally, FFP is generally indicated in acutely hemorrhaging patients as part of a massive transfusion protocol.

The benefit of plasma transfusion extends beyond its hemostatic effects to include reduction of vascular permeability and mitigation of inflammation after hemorrhagic shock. Severe trauma, in addition to other inflammatory conditions such as ischemia-reperfusion injury, diabetes, and sepsis, are known to result in vascular endothelial dysfunction. In vitro and in vivo ^, models of hemorrhagic shock demonstrate that plasma restores microvascular integrity, in part by repair of the endothelial glycocalyx. The mechanisms of action of FFP are the subject matter of current research, but may be attributed to soluble factors, of which over 1000 are found in plasma. Many of these soluble proteins are biologically active and have unknown functions.

Cryoprecipitate

Cryoprecipitate is collected as the precipitate of plasma after a freeze-thaw cycle and is enriched in factors VIII and XIII, von Willebrand factor, fibronectin, and fibrinogen. Administration of cryoprecipitate is principally indicated for fibrinogen deficiency or dysfibrinogenemia when there is clinical bleeding, trauma, acute disseminated intravascular coagulation, or before invasive procedures. Currently, the American College of Surgeons Committee on Trauma recommends transfusion of cryoprecipitate to maintain fibrinogen at 180 mg/dL or greater during massive transfusion in bleeding patients.

Plasma-derived products

Table 126.1 summarizes commonly used fresh and plasma-derived blood products. Prothrombin complex concentrate (PCC) contains concentrated vitamin K–dependent coagulation factors stored as a lyophilized powder. PCC comes as three-factor (containing factors II, IX, and X) and four-factor products (containing factors II, VII, IX, and X, in addition to the anticoagulant proteins—protein C, protein S, antithrombin, and heparin). Both three- and four-factor PCC have been shown to be superior to FFP for urgent reversal of acquired coagulation factor deficiency induced by vitamin K agonists and in correcting the coagulopathy of trauma, with four-factor PCC correcting elevated INRs more rapidly than three-factor PCC. Currently, there is extensive and increased use of PCC for off-label applications, such as reversing direct oral anticoagulants.

In addition to FFP and cryoprecipitate, fibrinogen concentrate is increasingly used in the management of hypofibrinogenemic states, depending on local availability. However, because of the low quality of published clinical evidence, the beneficial effect of fibrinogen concentrate remains under debate.

Recombinant blood products

Recombinant growth factors such as erythropoietin and granulocyte stimulating factor have had a major impact on managing anemia and neutropenia. Recombinant hemostatic factors, such as recombinant activated factor VII (rFVIIa), have improved the management of acquired hemophilias and other inherited bleeding diatheses. As rFVIIa tends to localize to areas of vascular injury once administered and may decrease the overall need for blood products in trauma patients, it has also been used off-label in the treatment of severe bleeding despite a lack of high-quality evidence for efficacy, as most experience has been observational and anecdotal.

Blood substitutes

Significant efforts have long been ongoing to develop substitutes for RBCs and platelets. Unfortunately, neither hemoglobin-based oxygen carriers nor chemical-based products such as perfluorocarbons have yielded optimistic results, and safety concerns have plagued clinical development. However, new research does suggest that these artificial oxygen carriers may have beneficial application in other areas, such as organ preservation for transplant surgery, sickle cell crisis, and brain oxygenation during circulatory arrest.