Transfusion of Plasma and Plasma Derivatives

C HAPTER

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TRANSFUSION OF PLASMA AND PLASMA DERIVATIVES: PLASMA, CRYOPRECIPITATE, ALBUMIN, AND IMMUNOGLOBULINS Matthew S. Karafin, Christopher D. Hillyer, and Beth H. Shaz Plasma and its derivatives are well-established clinical resources, but cost risk of infectious disease transmission, although rare, and other adverse effects mandate their appropriate use. Even to this day however, much still remains to be clarified regarding the appropriate clinical use of plasma products. The 2015 National Institute of Health-National Heart Lung and Blood Institute State of the Science Symposium revealed that significant and fundamental gaps in our knowledge regarding the most predictive clinical hemostatic tests (i.e., viscoelastic versus traditional coagulation tests), best products (i.e., frozen versus liquid plasma), new products (i.e., freeze dried plasma), and appropriate clinical indications/protocols for plasma product use remain. Plasma can be separated from red blood cells (RBCs) through centrifugation of whole blood at the time of collection, or can be collected by apheresis as a single product or as a by-product of platelet or RBC apheresis. Plasma can be processed into derivatives through cold ethanol fractionation (method of Cohn). In this chapter, the features and uses of plasma products, which include fresh frozen plasma (FFP), plasma frozen within 24 hours of phlebotomy (FP24), thawed plasma, liquid plasma, solvent detergent treated plasma (SD-plasma), pathogen-reduced/ inactivated plasma as well as plasma derivate, including cryoprecipitate-reduced plasma, cryoprecipitate, albumin, intravenous immunoglobulin (IVIg) and intramuscular immunoglobulin (Ig) are discussed. The use of plasma-derived clotting factor concentrates as well as coagulation factor concentrates that are genetically engineered as therapy for specific clotting factor deficiencies are discussed in Chapter 120.

PLASMA PRODUCTS Plasma is the acellular, fluid compartment of blood and it consists of 90% water, 7% protein and colloids, and 2% to 3% nutrients, crystalloids, hormones, and vitamins. The protein fraction contains the soluble clotting factors: fibrinogen, factor XIII, von Willebrand Factor (vWF), factor VIII primarily bound to its carrier protein vWF, and the vitamin K-dependent coagulation factors II, VII, IX, and X. Clotting proteins are the constituents for which transfusion of plasma is required. Plasma products include FFP, FP24, thawed plasma, SD-plasma, and pathogen reduced/inactivated plasma which can be used interchangeably. Notably, FFP and FP24 are both termed FFP in some countries outside of the United States.

FFP and FP24 Plasma frozen at −18°C or colder within 8 hours of donation (6 hours with the use of some storage bags after apheresis collection) can be labelled as FFP. This product may be stored up to 1 year before use, at which time it is thawed at 37°C over 20 to 30 minutes. A second type of frozen plasma, the most commonly used in the United States, is FP24 plasma. FP24 is frozen at −18°C or colder within 24 hours of collection. The difference between FFP and FP24, using historic data, is a reduction in the following factors: fibrinogen 12%, factor V 15%, factor VIII 23%, and factor XI 7%. More recently, a direct comparison between FFP and FP24 mean factor activity immediately postthaw revealed the following changes in activity levels: factor II 1744

0%, factor V +1%, factor VII −16%, factor VIII −15%, factor IX +6%, factor X 0%, vWF antigen activity +34%, vWF:ristocetin cofactor activity +22%, fibrinogen +29 mg/dL, antithrombin 0%, protein C −19%, and protein S −5%. A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity level is also equivalent in FFP, FP24, and cryoprecipitate-reduced plasma (discussed later). All of the factors evaluated in this study reveal that FP24 immediately postthaw had activities above the minimum activity required for safe surgical hemostasis (factor II 97%, factor V 86%, factor VII 89%, factor VIII 66%, factor IX 88%, factor X 94%, vWF:Ristocetin cofactor activity 123%, fibrinogen 309 mg/dL). Therefore, studies support that FFP and FP24 can be used interchangeably.

Thawed Plasma Coagulation factors are also well maintained in thawed FFP and FP24 stored at 1°C to 6°C for up to 5 days, termed thawed plasma. Studies show that during 5 days of storage, most clotting factors, including ADAMTS13, remain stable. However, there is evidence that activity levels fall significantly for factors V, VII, and VIII. A review by Eder and Sebock revealed that at day 5, factor V, VII, and VIII activity levels fell from day 1 on average by 16%, 20%, and 41%, respectively, if the FFP was derived from whole blood, and 9%, 4%, and 14%, respectively, if the FFP was derived via apheresis. Although some recent evidence suggests that thrombin generation may be slower in 5-day-old thawed plasma, the decrease in clotting factor activity for both FFP and FP24 is generally not considered to be of clinical significance, as the mean factor activity levels for 5-day-old thawed plasma remain above the minimum activity required for safe surgical hemostasis (on average, FFP: factor V 67%, factor VII 70%, factor VIII 43%; FP24: factor V 59%, factor VII 77%, factor VIII 48%). Stored thawed plasma improves patient care and is more cost-effective than frozen plasma because there is no preparation time required. This difference consequently results in a decreased turn-around time, and a substantially reduced wastage rate.

Liquid Plasma Liquid plasma is produced from whole blood within 5 days of the whole blood expiration date. Liquid plasma is maintained at 1°C to 6°C and stored for up to 26 days. It is deficient in labile clotting factors (i.e., factor V, VIII). It is used primarily for immediate treatment of acutely bleeding patients, especially where reversal of the effects of warfarin is required, as the vitamin K–dependent factors FII, FVII, F IX, and FX are relatively stable under these storage conditions. Liquid plasma remains rarely used in the United States, but studies in Europe demonstrate at least comparable efficacy to FFP in urgent situations.

Freeze-Dried Plasma (Lyophilized Plasma) Freeze-dried plasma is produced and pooled from 10 or fewer apheresis plasma donors. The plasma undergoes a cryodessication process

Chapter 115  Transfusion of Plasma and Plasma Derivatives

to form a 215 g powder in a sterile bottle. The plasma is then rehydrated for use via 200 mL of sterile water with soft agitation. While not in use yet in the United States (but used in Europe), the product is being actively investigated for use in military situations. Early studies suggest that the product is safe and efficacious for treatment of war injuries.

Cryoprecipitate-Reduced Plasma Cryoprecipitate-reduced plasma, also known as cryosupernatant or cryoreduced-plasma, is the remaining supernatant after the removal of cryoprecipitate from FFP, which is subsequently refrozen. This product is deficient in factor VIII, factor XIII, vWF, fibrinogen, and fibronectin. Cryoprecipitate reduced plasma is only indicated in the treatment of patients with thrombotic thrombocytopenic purpura (TTP), and thus cannot be used interchangeably with thawed plasma, FFP, or FP24. It can be thawed and stored for up to 5 days at 1°C to 6°C termed, thawed plasma cryoprecipitate reduced.

Solvent-Detergent Plasma (SD-Plasma) SD-plasma is a product manufactured from ≤2500 pooled plasma products that has been treated with solvent (tri-η-butyl phosphate)/ detergent (triton X-100) to inactivate lipid-enveloped viruses (HIV, hepatitis B, hepatitis C). The product is distributed in 200 mL containers, frozen at −18°C with a shelf life of 1 year. The coagulation factor levels are comparable to FFP and FP24, and SD-plasma has less viability between units. SD-plasma was recently approved by the U.S. Food and Drug Administration (FDA), and has the added advantage of a substantially reduced risk of transfusion-related acute lung injury (TRALI) and has a lower rate of allergic reactions.

Pathogen-Reduced/Inactivated Plasma Other pathogen-reduction methods have been developed including amotosalen photochemical treatment with ultraviolet (UVA) light, which has recently been FDA approved. Riboflavin-treated plasma with UVA light and methylene blue-treated plasma have also been developed, but these have not yet been FDA approved, but are approved in Europe. Studies in Europe show that these methods are also quite effective at reducing the risk of viral contamination, but are deficient in some clotting factors, such as fibrinogen and factor VIII (approximately 80% retention in comparison with control plasma).

Recovered and Source Plasma (Plasma for Manufacture) There are plasma products that are not used for transfusion, but are used for further manufacturing into plasma derivatives. These products include recovered plasma (liquid plasma and “plasma”) that are derived from whole blood and are sent to a manufacturer from a collection facility through a “short supply agreement”. Liquid plasma, as noted previously, is defined as plasma that is separated from whole blood at any time during storage at 1°C to 6°C, up to 5 days after the whole blood expiration date. “Plasma” is defined as liquid plasma that is frozen at −18°C or colder with a frozen shelf life of 5 years. Source plasma, a FDA licensed product, is collected by apheresis which is intended for further manufacturing. The Plasma Protein Therapeutics Association promotes safe collection and manufacturing practices of plasma derivatives. Source plasma can be collected more frequently under special donor programs; the donors can be compensated for their time, and can be collected in an open or closed system. Source plasma is frozen immediately in the United States and within 24 to 72 hours in Europe.

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Indications Most guidelines consistently support plasma transfusions for correcting multiple acquired coagulation factor deficiencies, as seen in liver failure or disseminated intravascular coagulopathy (DIC), massive transfusion, reversal of warfarin effect, and certain indications as a replacement fluid in therapeutic plasma exchange (Table 115.1). However, according to one recent metaanalysis, there are no published or ongoing trials regarding the optimal transfusion strategy for these indications. As there are currently no evidence-based laboratory value “triggers” for plasma administration, any recommendation needs to be carefully weighed against the patient’s presence, or risk, of bleeding. Plasma is typically indicated when prothrombin time (PT) and/ or partial thromboplastin time (PTT) are greater than 1.5 to 1.7 times normal paired with the presence of bleeding or anticipated bleeding. The justification for these current recommendations is that there is compelling evidence that plasma transfusions are ineffective in correcting mild to moderate abnormalities of coagulation screening tests. One study demonstrated that fewer than 15% of patients with a pretransfusion PT between 13.1 and 17.0 seconds had some correction after plasma transfusion, and less than 1% completely normalized. Another study found that minimally prolonged international normalized ratios (INRs) decreased with treatment of the underlying disease alone, and that the addition of plasma did not statistically change the INR over time. On the other hand, marked reductions in substantially elevated coagulation studies can occur with relatively modest plasma transfusion volumes. This variable response to plasma can be largely explained because of the nonlinear, exponential relationship between clotting factors activity levels and coagulation test results (Fig. 115.1). Audits of recent transfusion practices have consistently demonstrated that plasma product use is inappropriately high. Recent estimates suggest up to 83% (reported range: 10–83%) of plasma transfusions are not administered according to published guidelines. The most commonly cited reason for plasma administration is a preprocedural elevation in coagulation studies. This indication is not evidence-based, especially when the coagulation abnormality is mildmoderate. Moreover, plasma should not be used as a volume expander or as a source of nutrients. Clinical situations where plasma transfusions may be beneficial are further defined in the following sections.

Liver Failure Patients with liver failure may develop low levels of the vitamin K-dependent clotting factors (factors II, VII, IX, and X). These TABLE 115.1

Indications for Plasma Product Transfusion Indicated

Disseminated intravascular coagulation Liver failure Massive transfusion Multiple acquired coagulation factor deficiency Plasma infusion or exchange for thrombotic thrombocytic purpura and other thrombotic microangiopathies, diffuse alveolar hemorrhage, and catastrophic antiphospholipid syndrome Rapid reversal of warfarin effect when prothrombin complex concentrate is not available Replacement of an inherited single plasma factor deficiency for which no coagulation factor concentrate exists Not Indicated Burns Immunodeficiency Source of nutrients Volume expansion Wound healing

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Coagulation factors (%)

100

Zone of normal hemostasis (physiologic reserve) 50 30 Zone of therapeutic anticoagulation

PT (sec) 12 13 14 15 16 17 18 19 20 21 22 INR 1.0

1.3

1.7 2.0 2.2

3.0

Fig. 115.1  RELATIONSHIP BETWEEN FACTOR ACTIVITY LEVELS AND COAGULATION STUDIES. The general relationship between the concentration of coagulation factors and the result of PT and INR studies. The normalization of modest elevations in the INR required much larger volumes of plasma than would be expected and modest doses of plasma can result in marked changes in the INR when markedly elevated. The cause of this phenomenon can be explained by the nonlinear, exponential, relationship between coagulation factor concentration and standard coagulation test results. As shown earlier, small increases of coagulation factors correlate with marked changes in coagulation studies when coagulation factors are depleted. The opposite is true when the coagulation factors are at higher concentrations. INR, International normalized ratio; PT, prothrombin time. (Adapted from Levi M, Toh CH, Thachil J, Watson HG: Guidelines for the diagnosis and management of disseminated intravascular coagulation. Br J Haematol 145:24–33, 2009.

patients develop a prolonged PT/INR, PTT, and thrombin time. Fibrin split products may also be elevated in these patients, and in later stages, the fibrinogen level may be decreased. Prolongation of the PT and PTT has been correlated with both an increased risk of bleeding and mortality in these patients. Moreover, hemorrhage, most often secondary to an anatomic lesion, may be complicated by the coagulopathy resulting from these abnormalities. Patients with orthotopic liver transplantation complicated by preexisting severe liver disease and liver disease with DIC are two such examples that may require large plasma volumes. While elevations in coagulation tests are correlated with the incidence of bleeding in these patients, growing evidence now suggests that the PT and PTT are, in themselves, poor predictors of surgical bleeding. The reason for this lack of association may be twofold. First, PT and PTT values do not correlate well with plasma factor activity levels. One study identified that up to 50% of patients with abnormal coagulation tests had coagulation activity levels considered sufficient for adequate thrombus formation. Moreover, studies demonstrate that mild abnormalities in these coagulation tests do not correct—even with infusion of large quantities of plasma, because of the mathematical difficulty of infusing normal levels of factors into mildly deficient blood to get enough plasma to decrease the PT/PTT (see Fig. 115.1). Second, the lack of increased/ excessive bleeding noted in some patients with liver disease and elevated coagulation tests may be caused by a parallel reduction in anticoagulant proteins, such as proteins C and S. Therefore, patients with liver disease may not bleed as much as expected because they retain a homeostatic balance between coagulant and anticoagulant proteins. A growing body of evidence suggests that the use of plasma in the context of severe liver disease and perioperatively during liver transplant does not significantly improve outcome. One study demonstrated that appropriate plasma transfusions did not significantly alter thrombin generation in cirrhotic liver patients. Another study demonstrated in 293 patients who received plasma transfusions during hepatectomy that there was no significant difference in complication

rate or postoperative liver function tests between those who received plasma from those who did not. Two other studies showed a poor correlation between number of plasma transfusions, PT and PTT values, and number of RBCs transfusions needed during liver transplantation. Lastly, a randomized control trial revealed that intranasal desmopressin was both less expensive and as effective as plasma transfusions for liver disease patients with an INR between 2.0 and 3.0 undergoing minor surgery. As a result of these studies, authorities now suggest that the use of plasma be more limited in liver disease and hepatectomy patients. The transfusion of plasma in these patients should be guided by a combination of clinical assessment, the evidence and degree of bleeding, and by coagulation test results. Plasma products are currently not recommended prophylactically before a surgical challenge or liver biopsy in these patients. However, as noted previously, plasma transfusions may be considered when the PT/PTT is greater than 1.5 to 1.7 times normal, or if the INR is 2.0 or greater when the risk of bleeding is considered high.

Massive Transfusion Massive transfusion is generally defined as receiving 10 or more units of RBCs within 24 hours (or one blood volume). Trauma patients may arrive at the hospital with a prolonged PT (termed acute trauma induced coagulopathy, early trauma induced coagulopathy, or acute coagulopathy of trauma). Early trauma induced coagulopathy is associated with increased mortality and increased use of blood products. Trauma patients can also develop a secondary coagulopathy, termed the lethal triad, secondary to dilutional coagulopathy, acidosis and hypothermia. The dilutional coagulopathy is secondary to the administration of crystalloid and RBCs without coagulation factor support. Studies have shown that the early use of plasma and platelets in trauma patients undergoing massive transfusion appears to decrease the incidence of secondary coagulopathy (lethal triad) and improve survival in these patients. In addition, the early administration of tranexamic acid has been shown to reduce mortality in bleeding patients. Some experts have previously argued that plasma should be used only in the context of abnormal coagulation studies in a massively bleeding patient. However, recent studies have shown that this may not be the most effective approach. Because of the rapidity required to treat severely bleeding patients, standardized hospital-based massive transfusion protocols providing predetermined transfusions of RBCs, plasma, cryoprecipitate, and platelets are in use and have been associated with improved survival. Further, massive transfusion protocols identify who is responsible for different aspects of the patient’s care, what laboratory tests should be ordered and when, and what blood products should be prepared and at what intervals. Some protocols are laboratory based while others have preset blood product volumes and ratios, and lastly, some integrate both. Importantly, hospitals develop these protocols using a multidisciplinary team, defining quality measures with periodic review to adjust the protocol based on new evidence and data. The optimal ratio of RBCs and plasma in the context of massive transfusion is under active investigation. Multiple studies in both the military and civilian literature have shown a reduction in morbidity and mortality with a transfusion ratio of 1 unit of plasma for every 1 to 3 RBC units transfused in the context of severe posttraumatic bleeding. The Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study demonstrated that clinicians generally are transfusing patients with a blood product ratio of 1 : 1:1 or 1 : 1:2 (plasma:platelet:RBC) and that early transfusion of plasma (within minutes of arrival to a trauma center) was associated with improved 6-hour survival after admission. The recently published Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial was designed to compare the effectiveness and safety of a 1 : 1:1 transfusion ratio with a 1 : 1:2 transfusion ratio in patients with trauma who were predicted to receive a massive transfusion. This randomized clinical trial found no overall difference in survival based on

Chapter 115  Transfusion of Plasma and Plasma Derivatives

transfusion ratio, but did find that those who were randomized to receive more plasma (1 : 1:1 ratio) achieved hemostasis more frequently. Consequently, data support no advantage of 1 : 1:1 versus 1 : 1:2, and further study comparing 1 : 1:2 versus 1 : 1:3 is needed. Questions regarding best practice still remain. One European group has suggested that the use of prothrombin complex concentrate (PCC) and fibrinogen concentrates, instead of plasma, provide a safer alternative for massive transfusion patients. The increased use of whole blood, as an alternative to using the 1 : 1:1 component ratio, is being studied and has been shown to have similar efficacy in pilot trials. Other studies are investigating the early use of cryoprecipitate and the use of concentrated and/or lyophilized plasma. The optimal blood type for emergency plasma transfusions is also under active investigation. During the initial resuscitation phase of these patients, the patient’s blood type is often unknown. Emergency release plasma, traditionally group AB, is used until blood typing has been completed, and the plasma used can be switched to the patient’s identified ABO type. The theoretic advantage in using group AB plasma is its lack of anti-A and anti-B antibodies, thus theoretically avoiding the risk of acute hemolytic transfusion reactions. However, since AB plasma is the least common type of plasma, there is a possibility of shortages. Studies now support the use of group A plasma in massive support situations as the universal product, and have so far shown no increased risk to the recipient and no substantial effect on clinical outcomes. Some provide low titer, typically defined as less than 1 : 100, group A plasma while other do not titer group A plasma. Since patients typically receive group O RBCs and about 80% of the population is group O or group A, the risk of hemolysis is low. In the recent past, trauma patients would be provided primarily crystalloid and albumin, followed by component transfusion therapy based on specific transfusion “triggers.” A hemoglobin less than 8 g/dL for RBCs, a PT greater than 1.5 times normal for plasma, a platelet count less than 50,000/µL for platelet transfusions, and a fibrinogen less than 100 g/dL for cryoprecipitate were often used. These “triggers” have now been incorporated as part of some massive transfusion protocols as algorithms to guide therapy. In these protocols, component therapy is guided by rapid and regular laboratory value correlation. To improve the speed by which one can address coagulation abnormalities, some protocols now use thromboelastography (TEG) or other point-of-care tests. TEG technology provides a dynamic and global assessment of the coagulation process, and can provide rapid assessments of the patient’s platelet function, coagulation cascade, and fibrinolysis. The mechanism underlying TEG technology and the interpretation of TEG data are beyond the scope of this chapter. Currently, sufficient data are lacking to universally recommend the use of TEG in massive transfusion protocols. Massive transfusion in other conditions, such as liver, cardiac, or orthopedic surgery and obstetric hemorrhage, likely have a different pathophysiology and thus transfusion management of these patients may be different than trauma patients. Studies exploring the use of massive transfusion protocols in these situations are lacking, but institutions should have policies in place for rapid availability of blood products and laboratory testing.

Disseminated Intravascular Coagulation DIC may be secondary to sepsis, liver disease, hypotension, surgeryassociated hypoperfusion, trauma, obstetric complications, leukemia (usually promyelocytic), or underlying malignancy. Successful treatment of the underlying cause is paramount. Recent guidelines suggest, based on low quality evidence, that plasma therapy should not be initiated based on abnormal laboratory results alone. Rather, patients with DIC and bleeding, those requiring an invasive procedure, and those at risk for bleeding complications should be given plasma in amounts sufficient to correct or ameliorate the coagulopathy or hemorrhagic diathesis. Large volumes of plasma are often necessary to correct the coagulation defect in these patients. However, in

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patients with severe liver disease, bleeding, and DIC, plasma infusions often fail to normalize the PT and PTT.

Rapid Reversal of Warfarin Effect Warfarin inhibits the hepatic synthesis of vitamin K-dependent clotting factors (factors II, VII, IX, and X) by blocking the recovery of the form of vitamin K that is active in the carboxylation of these proteins. Warfarin therapy induces functional deficiencies of these factors, which correct within 48 hours after the discontinuation of warfarin if diet and vitamin K absorption are normal. The use of plasma in the context of warfarin anticoagulation is well established, but is becoming less relevant because of the availability of four factor PCC. Recent randomized control trials comparing PCC with plasma have demonstrated a similar clinical efficacy between the two products, but superior rate of INR normalization for those who receive PCC. Plasma is generally not indicated for warfarin reversal when the patient is not bleeding and when the patient has an INR <9, as vitamin K administration corrects the coagulopathy in 12 to 18 hours. In patients anticoagulated with warfarin who have active bleeding, require emergency surgery, or have serious trauma, however, the deficient clotting factors can be immediately provided by PCC, or plasma transfusions Plasma use may not be optimal in all situations of warfarin-induced bleeding, though, as large volumes of plasma might be required for adequate warfarin reversal, and lengthy infusion times, especially in those who are volume sensitive, might delay needed surgical intervention. Consequently, four factor PCC, which was approved for use by the FDA in April 2013, should be chosen as the first-line therapy for rapid reversal of life or limb threatening warfarin anticoagulation. For nonemergent or nonthreatening reversal, vitamin K can be administered. Studies have shown that PCC can reverse a warfarin-induced coagulopathy faster with lower mortality and less volume overload than plasma or vitamin K alone. Also, INR levels need to be closely followed to ensure warfarin reversal is sustained.

Thrombotic Thrombocytopenic Purpura and Other Thrombotic Microangiopathies In patients with TTP, plasma exchange (TPE) with plasma as the replacement fluid is life-saving. Plasma infusion or exchange is also critical in the treatment of individuals who have congenital TTP. TPE has decreased the mortality of TTP from over 90% to less than 10% (see Chapter 134). Six randomized control trials have demonstrated that TPE is most effective in patients who have an autoantibody to ADAMTS13. This is caused by both the removal of a patient’s plasma containing the inhibitor coupled with the addition of donor plasma containing the functional vWF-cleaving protease. The FDA has also approved the use of cryoprecipitate-reduced plasma for refractory TTP, defined as those who are unresponsive to plasma exchange with FFP. Some authorities advocate the use of cryoprecipitate-reduced plasma as a first-line therapy for TTP, as these products have a lower level of vWF than FFP, a comparable ADAMTS13 activity, and lower amounts of ADAMTS13–larger vWF multimer complexes. However, the most recent multicenter prospective randomized trial comparing exchange transfusion with plasma and cryoprecipitate reduced plasma for the initial treatment of TTP demonstrated equal efficacy between plasma and cryoprecipitate-reduced plasma for the initial therapy in TTP. Standard therapy involves daily TPE with plasma replacing 1.0 to 1.5 plasma volumes until the platelet count is above 150 × 109/L, and lactate dehydrogenase is near normal for 2 to 3 consecutive days. Treatment should be initiated immediately or at least within 24 hours of diagnosis, and if TPE is not available to initiate treatment, plasma infusions can be used until TPE is available. The total number of treatments required is variable and is based on each individual’s clinical response, but studies have shown that the median number of TPEs needed to establish hematologic recovery is about 7 to 8.

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TPE is not indicated in the treatment of individuals with diarrhea associated hemolytic uremic syndrome (HUS) (also termed thrombotic microangiopathy, Shiga toxin mediated) unless there are severe neurological symptoms. Seven randomized control trials were performed evaluating the efficacy of TPE for typical cases of HUS. These trials found that the use of plasma was not superior to supportive therapies alone. TPE with plasma replacement fluid, however, is currently indicated in diarrhea-negative (atypical) HUS (aHUS), which is caused by a number of inherited and sporadic conditions that lead to the uncontrolled activation of the alternative complement system (i.e., deficiency or autoantibody to complement factor H). A complete discussion of aHUS is beyond the scope of this chapter. Typically, all patients diagnosed with aHUS are empirically treated with TPE or plasma transfusions until underlying disease or mutation is further defined, which then determines treatment. TPE has been theoretically proposed to effectively remove the potentially causative autoantibody or mutated circulating complement regulator, while replacing absent or defective complement regulators. The reported clinical response varies depending on the underlying cause, however. For some causes of aHUS, plasma infusion can be initiated. Recently, Eculizumab, a humanized monoclonal antibody against C5, has been shown to be an effective alternative treatment for some causes of aHUS (see Chapter 134). TPE with plasma replacement may also be indicated in other thrombotic microangiopathies. Some medications cause thrombotic microangiopathies that require plasma exchange. Current examples include ticlopidine and clopidogrel, and potentially cyclosporine or tacrolimus. Lastly, TPE with plasma may also be used in the treatment of thrombotic microangiopathy associated with stem cell transplantation. Plasma as replacement fluid, either partially or completely, for TPE is used in other diseases with risk of hemorrhage caused by the resulting coagulopathy, such as diffuse alveolar hemorrhage, liver failure, and perioperatively.

Dosage One unit of plasma derived from a unit of whole blood contains 200 to 280 mL. When plasma is collected by apheresis, as much as 800 mL can be obtained from one individual (“jumbo” plasma units), but the majority of units clinically used have a volume around 250 mL. On average, there is 0.7 to 1 unit/mL of activity of each coagulation factor per milliliter of plasma and 1 to 2 mg/mL of fibrinogen. The appropriate dose of plasma may be estimated from the plasma volume, the desired increment of factor activity, and the expected half-life of the factor being replaced (i.e., factor VII has a half-life of only 4–6 hours, and thus plasma doses should be repeated every few hours if replacing factor VII in a patient with factor VII deficiency). Alternatively, the plasma dosage may be estimated as 10 to 15 mL/kg, and ideally should be ordered as the number of milliliters to be infused. The frequency of administration depends on the clinical response to the infusion and correction of laboratory parameters. Moreover, plasma infusions should be given as close to the time as it is needed to allow for its maximum hemostatic effect if given preprocedure. A recent one-year evaluation of 10 U.S. hospitals revealed that the current median dose of plasma was 2.0 units with 15.2% receiving only 1 unit. The median weight-adjusted plasma dose was only 7.3 mL/kg with only 29% of doses being at least 10 mL/kg and 15.5% being 15 mL/kg. Based on these findings, a large proportion of patients in the United States are likely being underdosed.

Compatibility Plasma is screened for unexpected RBC antibodies during product testing and should be ABO-type compatible for transfusion (see later). Notably, group AB plasma is universally compatible with all patients and group O plasma is only compatible with patients with group O RBCs.

Prophylactic Use of Plasma Studies have shown that prophylactic administration of plasma to nonbleeding recipients with abnormal coagulation studies (i.e., PT, aPTT, INR) is unlikely to produce a clinical benefit and unnecessarily exposes the patient to the risks of plasma transfusion. Moreover, systematic reviews of whether a prolonged PT or aPTT even predicts bleeding found no significant difference in the risk of bleeding between patients with a prolonged PT or aPTT and those with normal clotting parameters in the setting of bronchoscopy, central vein cannulation, angiography, or liver biopsy. Despite this ambiguity, a number of randomized control trials and metaanalyses have evaluated the efficacy of the prophylactic use of plasma products to reduce the risk of bleeding. One trial, the Northern Neonatal Nursing Initiative Group Trial, randomized 776 neonates, and evaluated whether plasma transfusion prophylaxis could prevent intraventricular hemorrhage in comparison with volume expanders (gelofusine or dextrose-saline). In a second large randomized clinical trial, 275 patients were randomized to see whether plasma transfusions could prophylactically prevent bleeding in acute pancreatitis patients. Neither large study showed clinical benefit of prophylactic plasma use. In one systematic review, 55 other randomized clinical trials were reviewed and evaluated. Only 17 of these 55 involved a control group that did not receive plasma. Overall, like the two largest studies, the results of these randomized control trials failed to show evidence for the efficacy of prophylactic plasma use across multiple clinical and laboratory outcomes. Similarly, a second metaanalysis evaluated 25 independent studies of minor surgical procedures and found that there was no significant difference in bleeding risk between those who did and did not have a coagulopathy. Despite this evidence, current recommendations still indicate that a pretransfusion INR of ≥1.5 to 1.7 be used as a transfusion trigger, as the prophylactic use of plasma is theoretically justified when the clinical risk of bleeding is greater than potential harms of using plasma.

Plasma Product ABO Type Patient ABO type O A B AB

O Yes No No No

A Yes Yes No No

B Yes No Yes No

AB Yes Yes Yes Yes

Yes = compatible blood types No = incompatible blood types

Adverse Events Plasma transfusion is associated with a number of infectious and noninfectious adverse events. Transfusion transmitted diseases traditionally include HIV, hepatitis B, and hepatitis C (Chapter 120), which are currently rare. Noninfectious risks include allergic reactions, TRALI, transfusion-associated circulatory overload (TACO), and hemolytic reactions (Chapter 119).

Transfusion-Related Acute Lung Injury TRALI is noncardiogenic pulmonary edema associated with the transfusion of blood products. TRALI is usually caused by neutrophil and pulmonary endothelial activation, usually caused by transfused donor white cell antibodies, including human leukocyte antigen (HLA) antibodies and human neutrophil antigen (HNA) antibodies. These donor antibodies react with the recipient’s white cells in the pulmonary vasculature causing leukoagglutination, activation of the

Chapter 115  Transfusion of Plasma and Plasma Derivatives

complement cascade, cytokine release, and pulmonary edema. Approximately 5% of TRALI is caused by the opposite mechanisms, which are recipient white cell antibodies against transfused donor white cells. Nonimmune mechanisms are also postulated to mediate TRALI, including bioactive lipids and CD40 ligand. TRALI is the most common cause of transfusion-associated mortality in the United States and is usually associated with transfusion of blood products containing large volumes of plasma containing white blood cell antibodies. Patients at higher risk include those with shock, chronic alcohol abuse, positive fluid balance, higher peak airway pressure, and current smoker. Signs and symptoms appear within 2 to 6 hours of transfusion and include respiratory distress with dyspnea, tachypnea, hypoxia, fever, tachycardia, and hypotension. Bilateral pulmonary infiltrates on chest x-ray may be seen with no evidence of left atrial hypertension. In cases of suspected TRALI, the transfusion should be discontinued. Medical management is primarily supportive, commonly with supplemental oxygen and endotracheal intubation, if needed. Diuresis is not indicated, and the role of steroids is unclear. The majority of patients improve within 2 days, although TRALI has a 5% to 25% mortality rate. Multiple strategies have been implemented to reduce the risk of TRALI and have resulted in a substantial decline in its incidence. First, donors implicated in prior TRALI reactions are deferred from further blood donation. Second, multiparous female donors can be tested for HLA and HNA antibodies, and blood products with high volume plasma (i.e., plasma and apheresis platelets) are not made from those with high-titer antibodies. Third, plasma supplied to hospitals for transfusion can be only from male donors while the female plasma is diverted for fractionation. Currently, these strategies have reduced the risk of TRALI from 1 : 4000 to 1 : 12,000 without significantly reducing blood product availability.

Allergic Reactions Allergic transfusion reactions occur when preformed recipient antibodies bind to transfused allergens. Allergic transfusion reactions occur in approximately 1% to 3% of plasma transfusions. Anaphylactic reactions occur in approximately 1 in 20,000 to 1 in 50,000 transfusions. The majority of allergic transfusion reactions are mild. Mild reactions consist of urticaria with or without generalized pruritus or flushing. More severe symptoms include hoarseness, stridor, wheezing, dyspnea, hypotension, gastrointestinal symptoms, and shock. Mild reactions can be treated with antihistamines, while more severe reactions can be treated with epinephrine, H1-receptor antagonists, and steroids. Anaphylactic reactions may be secondary to anti-IgA, usually found in rare patients with IgA deficiency (0.13% of the population). Patients who have severe allergic reactions should be tested for IgA deficiency and the presence of anti-IgA. If anti-IgA is identified, the patient should receive plasma products from IgA-deficient donors or washed RBC and platelets products. Premedication with antihistamine is used to mitigate allergic transfusion reactions and is indicated in patients who have multiple prior or moderate allergic reactions. Unlike platelet products, however, which can be washed or concentrated before administration, there are currently no other preventative measures, other than premedication, to diminish the risk or severity of allergic reactions in plasma transfusion recipients. Consequently, oral premedication with antihistamines can be given 30 to 60 minutes before a transfusion, while intravenous premedication can be given 10 minutes before a transfusion in patients with a history of allergic reactions to plasma products.

Transfusion-Associated Circulatory Overload TACO results from vascular fluid volume overload following the transfusion of blood products, and is most common in very young or elderly patients with cardiac dysfunction or positive fluid balance.

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TACO is also likely underdiagnosed and underreported. Studies show that the mean age of patients who develop TACO range from about 70 to 85 years. Additional known risk factors for TACO include larger volumes of transfusion, greater plasma transfusion volume, and a faster transfusion rate. The incidence of TACO is unknown, but it is increasingly recognized clinically. Studies have reported the incidence to range from 1 in 356 to 1 in 10,000 blood products transfused or 1% to 8% of transfusion recipients, depending on the study population and data collection methodology, and are currently associated with a mortality rate of 5% to 15% in the United States. Symptoms include dyspnea, orthopnea, cough, chest tightness, cyanosis, hypertension, and headache. Symptoms usually present at the end of transfusion but may occur up to 6 hours posttransfusion. Diagnosis is based on the presence of cardiogenic pulmonary edema. Management includes discontinuing transfusion, diuretic therapy, oxygen supplementation, and sitting the patient upright. Avoiding rapid transfusion can prevent TACO, unless clinically indicated. Transfusions should be administered slowly, usually 1 mL/kg/h, particularly in patients at risk for TACO.

CRYOPRECIPITATE Cryoprecipitate is prepared from 1 unit of FFP thawed at 4°C. The precipitate is then refrozen and stored at −18°C or colder for 1 year. Cryoprecipitate, volume of 10 to 15 mL, contains 80 to 100 units of factor VIII, 100 to 250 mg of fibrinogen, and 50 to 60 mg of fibronectin as well as vWF and factor XIII. Cryoprecipitate takes 10 to 15 minutes to thaw at 30°C to 37°C, and then requires pooling before infusion. Prepooled (pooled before storage) cryoprecipitate products are now available, easing the burden of preparation on the transfusion services. Once pooled and thawed, cryoprecipitate is maintained at 20°C to 24°C and outdates in 4 hours (6 hours if unpooled or pooled in a closed system).

Indications Cryoprecipitate is used predominantly to treat bleeding associated with fibrinogen deficiency (Table 115.2). Cryoprecipitate should not be used to treat factor XIII, vWF, and factor VIII deficiencies, as virally inactivated factor concentrates are available. Human fibrinogen concentrate is also available and FDA approved, which is primarily used for congenital fibrinogen factor deficiency in the United States and broader indications in Europe. Like plasma, recent studies also indicate that actual administered doses of cryoprecipitate vary widely, suggesting inconsistent practice and uncertainty over the evidence informing optimal use. One large audit, for instance, demonstrated that across 25 Canadian hospitals and 4370 units of cryoprecipitate transfusions, only 24% of transfusions were considered clinically appropriate, and 34% of cryoprecipitate transfusions were deemed inappropriate according to published national guidelines (i.e., TABLE 115.2

Administration of Cryoprecipitate

Indicated Congenital afibrinogenemia if fibrinogen concentrate unavailable Dysfibrinogenemia Factor XIII deficiency Fibrinogen deficiency Massive transfusion Reversal of thrombolytic therapy Possibly Indicated Amniotic fluid embolism (used as last resort to replace depleted fibronectin) Snake bites Uremic bleeding

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Transfusion Medicine Advisory Group of British Columbia, Canada Guidelines for cryoprecipitate transfusion).

Fibrinogen Deficiency Fibrinogen deficiency is the primary indication for cryoprecipitate transfusion. The deficiency may be caused by congenital afibrinogenemia or dysfibrinogenemia, severe liver disease, DIC, or massive transfusion. Patients with the later indications often have concomitant decreases in clotting factor levels and require the coadministration of plasma products. It is important to obtain fibrinogen measurements because levels less than 100 mg/dL cause prolongation of the PT and PTT, despite adequate clotting factor replacement. Very low levels of fibrinogen occur during liver transplantation (<100 mg/dL), where transfusion support with cryoprecipitate is vital. A specific purified human fibrinogen concentrate is now available, and may represent a safer alternative for direct fibrinogen replacement in isolated fibrinogen deficiencies, such as inherited hypofibrinogenemia. Fibrinogen concentrates undergo viral inactivation and have a standardized fibrinogen content; these are used preferentially over cryoprecipitate in some countries, but studies have not demonstrated a clinical benefit over cryoprecipitate. In the United States, fibrinogen concentrate is FDA approved for treatment of bleeding in patients with congenital fibrinogen deficiency.

Fibrin Glue/Sealant Fibrin glue/sealant results from the mixture of a fibrinogen source (from plasma, platelet-rich plasma, or allogeneic/autologous cryoprecipitate) with a thrombin source (bovine, human, or recombinant). The enhanced local hemostasis achieved by the sealant product is through the action of thrombin on fibrinogen. “Fibrin glue” is a non–FDA-approved thrombin/preparation, and it has been widely used in Europe many years. Fibrin and thrombin sealants are FDAapproved alternatives to fibrin glue and are advantageous over locally made fibrin glues, because of standard dosing. Fibrin and thrombin containing glues/sealants can be used for multiple surgical purposes, including as a topical hemostat (creating a blood clot to halt bleeding), as a sealant (agents to prevent leakage of potentially nonclotting fluids, i.e., cerebrospinal fluid), or as an adhesive (bonds different tissues together). Multiple fibrin or thrombin containing products are now FDA approved for use. The safety profile of each product differs depending on the product components and source. Bovine thrombin has been reported to cause anaphylaxis (because of bovine allergies), coagulopathy through formation of antibodies to factor V or II, and rarely death caused by severe systemic hypotensive reactions. Consequently, bovine products have an FDA mandated black-box warning on their package inserts. Pooled human plasma sources have the potential risk of viral or prion disease transmission. Reports indicate that hepatitis A and parvovirus B19 are particularly difficult to remove from these products despite current cleansing and filtration methods, and it is recommended that patients be counselled about this risk. Recombinant products, while eliminating the risk of infectious transmission or antibody formation, may also cause allergic reactions because of the hamster or snake proteins used to manufacture the product. Lastly, autologous fibrin clot preparations have been used, although the infectious risks (e.g., HIV and hepatitis) associated with the use of heterologous fibrin glue are eliminated by replacement with the autologous source, but are resource intensive. Given the current safety of the blood supply, the infectious risks are extremely low, particularly for pathogen inactivated products. Alternatively, albumin mixed with glutaraldehyde has been used to form both an effective sealant and adhesive. The FDA has currently approved an albumin-based product to seal large blood vessel anastomoses and to reattach layers of the aorta in the context of an aortic dissection. Other successful reported uses include as

a sealant in breast cancer surgery, and to reduce air leaks in lung volume reduction procedures. Side effects of this compound can be significant, however, and include nerve and muscle necrosis, sinoatrial node damage, calcium metabolism abnormalities, mucosal and skin irritation, adhesive emboli, limitation of aortic growth, and pseudoaneurysms.

Uremic Bleeding Abnormal bleeding is a common complication of uremia and is primarily caused by platelet dysfunction and defective interaction with endothelium. Use of cryoprecipitate as a source of vWF has been speculated to correct the platelet dysfunction. However, cryoprecipitate has been shown not to affect platelet aggregation in vitro, but does shorten the bleeding time. In 1980, a single study published in the New England Journal of Medicine led to the widespread, but temporary, use of cryoprecipitate for the treatment of uremic bleeding. Since that time, variable response reports have been published. Numerous alternative strategies are currently available for the prevention and treatment of uremic type bleeding including dialysis, erythropoietin, RBC transfusion, desmopressin, and conjugated estrogens, and, as such, cryoprecipitate is now rarely used in the prevention or treatment or uremic bleeding.

Massive Transfusion While most studies regarding massive transfusion evaluate the use of platelets and plasma, some studies suggest that regular doses of cryoprecipitate may also help improve survival. In general, the current use of cryoprecipitate in massive support is not standardized and the use is based on theoretic efficacy. According to the recently published PROMMTT study, there are wide differences (7–82%) in the use of cryoprecipitate at U.S. level 1 trauma centers, and inclusion of cryoprecipitate in massive transfusion protocols vary significantly. Specifically, some PROMMTT sites used cryoprecipitate after a certain number of RBC units infused, while others used fibrinogen triggers, such as 100 mg/dL. While the PROMMTT study found no significant differences in mortality between those that did and did not receive cryoprecipitate, other studies have shown benefit. One study found that a high transfusion ratio involving cryoprecipitate in 214 massive transfusion patients resulted in improved 30-day survival (66% versus 41%). Another key study found that maintaining a ≥0.2 g fibrinogen/RBC (10 units of cryoprecipitate used for every 10 units of RBCs) unit ratio resulted in significantly higher survival rates (76% versus 48%). Lastly, military trauma patients in the MATTERs II study who received a combination of cryoprecipitate and Tranexamic acid had the lowest observed mortality despite high injury severity scores (odds ratio, 0.34). While a small randomized feasibility study has been performed (CRYOSTAT trial), and demonstrated that cryoprecipitate can be prepared early during trauma resuscitation, larger randomized prospective clinical trials are still needed. Consequently, while still under investigation, current data tentatively support the use of cryoprecipitate in the context of massive transfusion protocols, however cryoprecipitate remains indicated in the treatment of hypofibrinogenemia. See box “Severe Maternal Hemorrhage.”

Dosage The dosage of cryoprecipitate is calculated on the basis of the amount of fibrinogen present in 1 unit of cryoprecipitate, the plasma volume, and the desired increment. The difficulty in determining the correct amount to administer is primarily caused by variability in the fibrinogen content of cryoprecipitate, secondary by variability in donors and component processing and preparation. The goal of therapy should be to maintain the measured fibrinogen at greater than 100 mL/dL, although increasing studies and some consensus recommendations

Chapter 115  Transfusion of Plasma and Plasma Derivatives Severe Maternal Hemorrhage Major obstetric hemorrhage is a leading cause of maternal morbidity and mortality, and is preventable and/or treatable. Significant obstetric hemorrhage is defined as active bleeding >1000 mL within the 24 hours following birth that continues despite the use of initial measures including first-line uterotonic agents and uterine massage. Early assessment and aggressive treatment of postpartum hemorrhage (PPH) are important for reducing morbidity and mortality rates. A critical first step in managing PPH is rapid recognition that clinically significant bleeding has occurred, with effective communication of the situation to the appropriate team members, both clinical and laboratory staff. Subsequent measures include immediate resuscitation with definitive action to arrest the bleeding (obstetric, surgical, and/or hematologic) and ongoing assessment and monitoring of the response to treatment. In these cases, blood ordering protocols specific to obstetric patients may be helpful. A massive transfusion protocol, similar to that seen in acute trauma patients ensures sustained availability of blood products while the bleeding remains uncontrolled. Unique to maternal hemorrhage, hypofibrinogenemia is an important predictor for the later development of severe bleeding. Consequently, point-of-care technologies, such as thromboelastography and rotational thromboelastometry, in addition to fibrinogen levels can identify decreased fibrin clot quality during PPH, which correlate with low fibrinogen levels and can assist in transfusion management. Early administration of 1 to 2 g tranexamic acid is also recommended, followed by an additional dose in cases of ongoing bleeding. Early fibrinogen replacement using an appropriate dose of cryoprecipitate may also be beneficial in these cases.

have revised target levels to at least 150 to 200 mg/dL, or a TEG Maximum clot firmness (MCF) reading of 6 to 8 mm. It is estimated that a dose of 8 to 10 units of cryoprecipitate will increase the fibrinogen in a 70 kg adult by 50 to 70 mg/dL, but how this dose affects a TEG is unclear. Dosing frequency should be determined based on clinical and laboratory responses, as factor XIII and fibrinogen are very stable proteins. Specifically, the half-life of fibrinogen is 4 days, and factor XIII has a half-life of 9 days.

Compatibility Cryoprecipitate can contain minimal anti-A and/or anti-B antibodies and, as such, ABO and D compatibility is not necessary for most adult and pediatric patients.

Adverse Events Cryoprecipitate has similar adverse event risk as other blood products, including transfusion-transmitted diseases, hemolytic reactions and allergic reactions. Since it contains less plasma and no leukocytes, febrile and allergic reactions are less likely to occur.

ALBUMIN Albumin, an important plasma protein, contributes primarily to the maintenance of plasma colloid oncotic pressure; it is also involved in the transport of numerous substances, such as unconjugated bilirubin, various hormones, and drugs. Albumin also has an established role in acid-base function, free radical scavenging, is antiapoptotic, antithrombotic, and has positive and negative effects on vascular integrity. The human body content of albumin is 4 to 5 g/kg, and is responsible for 80% of the osmotic pressure of human plasma. Albumin is clinically available in four forms: 5% solution in saline; 25% solution in distilled water; albumin conjugated with polyethylene glycol; and purified protein fraction, which is 5% total protein (88% albumin and 12% globulins). These products are heat-treated and albumin has not been documented to transmit infectious diseases (single outbreak occurred with albumin transfusion-associated hepatitis B with purified protein fraction in 1973).

TABLE 115.3

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Administration of Albumin

Indicated After large-volume paracentesis Nephrotic syndrome resistant to potent diuretics Ovarian hyperstimulation syndrome Volume/fluid replacement in plasmapheresis Possibly Indicated Adult respiratory distress syndrome Cardiopulmonary bypass pump priming Fluid resuscitation in shock/sepsis/burns Neonatal kernicterus/hyperbilirubinemia To reduce enteral feeding intolerance Not Indicated Correction of measured hypoalbuminemia or hypoproteinemia Nutritional deficiency, total parenteral nutrition Preeclampsia Red blood cell suspension Simple volume expansion (surgery, burns) Wound healing Investigational Cadaveric renal transplantation Cerebral ischemia Stroke Common Usages Cardiopulmonary bypass, pump priming Extensive burns Hypotension Intraoperative fluid requirement exceeding 5–6 L in adults Labile pulmonary, cardiovascular status Liver disease, hypoalbuminemia, diuresis Nephrotic syndrome, proteinuria, and hypoalbuminemia Plasma exchange Premature infant undergoing major surgery Protein-losing enteropathy, hypoalbuminemia Resuscitation Serum albumin <20 g/dL

Indications A decrease in measured plasma albumin is found in many situations, including chronic liver disease, chronic renal failure, sepsis, malignancy, burns, critical illness, severe head trauma, and hemorrhage, and is often, in itself, not a clinically significant concern. Mild edema arising from hypoalbuminemia does not require albumin therapy. However, inadequate synthesis, as seen in severe liver disease and severe malnutrition, or excessive loss, as seen in nephrotic syndrome and protein-losing enteropathy, can lead to significant hypoalbuminemia with intravascular volume depletion, anasarca, ascites, and pleural effusions. Hypoalbuminemia is associated with poor clinical outcome in some studies, yet correction of low serum albumin levels in critically ill patients does not improve outcome measures such as mortality, duration of intensive care unit (ICU) and hospital stay, or mechanic ventilation. Historically, albumin had a broader use (i.e., nutritional support, correction of hypoalbuminemia, volume replacement), but recent studies support its benefit in fewer situations, including nephrotic syndrome resistant to potent diuretic therapy, after large-volume paracentesis, and in ovarian hyperstimulation syndrome (OHSS) (Table 115.3).

Intravascular Volume Expansion As noted, albumin provides the majority of plasma colloid oncotic pressure. Infused albumin provides colloid oncotic pressure; however, 50% of the infused protein is lost to the extravascular fluid

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compartment within 4 hours. Crystalloid may also provide volume expansion and is more quickly redistributed into total body fluids. Studies investigating the use of albumin in various situations including volume expansion during and after surgery, as priming solution in cardiopulmonary bypass, or in maintaining colloid oncotic pressure, found no clinical benefit compared with controls. In 1998, the Cochrane Injuries Group performed a systematic review of randomized control trials in albumin treatment of critically ill patients and concluded that there was no evidence that albumin use for volume expansion reduces mortality in patients. They also suggested that albumin increases mortality, but this conclusion was not confirmed in later randomized control trials or subsequent metaanalyses. The SAFE trial found in 6997 patients across 16 ICUs that there was no difference in survival between those ICU patients who received albumin versus normal saline. In another randomized study, the SAFE trial investigators found that albumin use was associated with a trend toward better outcomes in patients with severe sepsis 2-year postrandomization. A smaller prospective study further revealed that albumin was at least equivalent to plasma in clinical endpoints (perioperative/postoperative RBC transfusions, postoperative blood loss, duration of ICU stay, major complications) as a plasma expander in the context of pediatric craniofacial surgeries. One conclusion from these prospective randomized trials is, contrary to previous reports, the use of albumin is at least clinically equivalent to saline or plasma for intravascular volume resuscitation in some clinical settings. Moreover, the Italian Society of Transfusion Medicine and Immunohematology recently recommended that albumin may be useful for hypovolemia in some patients with hemorrhagic shock, patients undergoing major surgery, such as cardiac surgery, patients with severe burns, and patients postliver transplant when crystalloids and other colloids did not provide adequate clinical benefit.

Hypoalbuminemia Low serum albumin is an independent predictor of morbidity and mortality in many clinical settings. However, correction of low serum albumin levels in ill patients does not improve outcome measures such as mortality. However, two randomized controlled studies showed that correction of hypoalbuminemia did improve respiratory, cardiovascular, and central nervous system function. Current guidelines support the use of albumin to correct hypoalbuminemia for patients with ascites, large volume paracentesis, hepatorenal syndrome, and spontaneous bacterial peritonitis. Recent studies with albumin infusions have also been done in end-stage liver disease patients for hypoalbuminemia. However, results are less encouraging, with studies indicating no additional benefits or reduction in morbidity.

Cirrhosis The use of albumin in cirrhotic patients dates to before 1950. In this setting, albumin was recommended for temporary improvement in hyponatremia, spontaneous bacterial peritonitis, or prevention of the complications associated with paracentesis, including volume shifts and hyponatremia, as noted earlier. Several studies demonstrated that after large-volume paracentesis (>5 L), hyponatremia and renal insufficiency were improved with albumin infusion compared with other volume-expanding agents. Moreover, a single randomized control trial of albumin use in cirrhotic patients with spontaneous bacterial peritonitis revealed that albumin administration with antibiotics resulted in reduced mortality and a reduced risk of renal failure in comparison with antibiotic use alone.

Nephrotic Syndrome Albumin has been used to increase colloid oncotic pressure with the intention of increasing diuresis via increasing vascular pressure at the level of the glomerulus. Several studies have shown that albumin use

in this context have resulted in no clinical benefit. However, other studies have suggested that albumin use is associated with increased hypertension, respiratory distress, and electrolyte abnormalities. Consequently, the current recommended use of albumin for nephrotic syndrome patients is limited to patients in whom diuretic therapy is poorly tolerated or ineffective or in those with massive ascites or anasarca.

Ovarian Hyperstimulation Syndrome OHSS is usually a result of iatrogenic administration of human chorionic gonadotrophin (hCG) to induce ovulation. OHSS is typified by enlarged ovaries which release vascular endothelial growth factor that can result in increased capillary permeability. This, in turn, leads to a fluid shift out of the intravascular compartment to the abdominal/pleural spaces resulting in ascites and hypovolemia. In the most severe form, the patient can develop tense ascites, oliguria, dyspnea, hemodynamic instability, and thromboembolism. Treatment includes fluid restriction, analgesics, and close monitoring; occasionally hospitalization may be necessary. Mild OHSS occurs in approximately one-third and moderatesevere in approximately 5% of women receiving exogenous hCG. Increased risk of OHSS includes young age, low body weight, polycystic ovarian syndrome, high dose hCG, high or rapid rise in estradiol level, and previous history of OHSS. In addition, the risk is proportional to the number of developing follicles and number of oocytes retrieved. Moderate-severe OHSS can be mitigated by closely monitoring women during treatment and subsequently withholding or reducing hCG administration when there is a large number of intermediate size developing follicles present or when estradiol levels are elevated. In 2011, the Cochrane collaboration systematically reviewed eight randomized clinical trials of albumin administration in OHSS, and concluded that there is only a borderline statistically significant decrease in the incidence and severity of OHSS when albumin was administered during oocyte retrieval in high-risk women. In contrast, the metaanalysis further revealed that the use of hydroxyethyl starch (HES) resulted in a markedly decreased incidence of severe OHSS. In addition, Bellver et al. published a large randomized trial that demonstrated no difference in moderate-severe OHSS when 40 g of albumin was administered after the retrieval of 20 or more oocytes. Only one (nonrandomized) study to date has compared human albumin and 6% HES. This study concluded in 16 patients with severe OHSS that patients who received HES had a higher urine output, needed less abdominal paracentesis and drainage of pleural effusions, and had a shortened hospital stay than patients who received albumin. Therefore, while still clinically used, albumin may be inferior to other therapies in the prevention of OHSS.

Therapeutic Apheresis Albumin is the replacement fluid of choice for many apheresis indications. Albumin reduces the risk of adverse events during apheresis procedures by reducing the risk of viral transmission, allergic reactions, and TRALI in comparison to plasma use (see plasma section). Albumin can also be used in combination with saline during apheresis procedures, but excessive use of saline results in hypotensive reactions. Albumin is also indicated if large (>15% of the total blood volume) blood volumes are removed to prevent hypotensive reactions in other therapeutic apheresis procedures (leukapheresis, plateletpheresis). While albumin is generally well tolerated in therapeutic apheresis patients, albumin use can result in significant hypotension, bradycardia, and flushing in patients receiving angiotensin converting enzyme inhibitor (ACE) therapy. ACE inhibitors prevent the patient’s ability to metabolize bradykinins that are present in the albumin and activated during the apheresis procedure. In patients taking ACE inhibitors, symptoms can be prevented by using plasma, or halting ACE inhibitor use and delaying the start of apheresis therapy.

Chapter 115  Transfusion of Plasma and Plasma Derivatives

Emerging Indications Serum albumin has been shown to be a free radical scavenger. Because of this function, some have recommended albumin as an adjuvant therapy in patients with sepsis. There are no confirmed data on the benefits of albumin therapy in this patient population, however. In other conditions associated with systemic inflammation such as acute lung injury or acute respiratory distress syndrome, albumin therapy use was found to improve oxygenation and hemodynamic status.

Dose The volume and speed of administration should be determined by the patient’s volume status, condition, and response to the product. In an adult, the total daily dose should not exceed the theoretical amount present in normal plasma (2g/kg/day), in the absence of acute hemorrhage. In the pediatric population, albumin dose again depends on the patient’s condition, but 0.5 to 1.0 g/kg/dose with a maximum dose of 6 g/kg/day could be used as a general guideline. Albumin 5% is oncotically equivalent to normal human plasma. Albumin 25% provides less infusion volume per amount of albumin and is usually administered to patients with fluid or sodium intake restriction. Albumin 25% expands the blood volume by 3.5 times by drawing fluid into the intravascular space.

Adverse Effects Albumin is a plasma derivative used widely and associated with rare adverse reactions. Allergic reactions, including urticaria, may be encountered. Changes in vital signs (heart rate, blood pressure, respiration rate), nausea, emesis, and fever/chills have also been rarely reported. Volume overload and dilutional anemia as well as hypocalcemia may occur. Albumin has not been associated with transfusiontransmitted diseases.

INTRAVENOUS IMMUNOGLOBULIN IVIg is prepared by fractionation of large pools of human plasma. There are numerous preparations available in the United States and throughout the world. Subcutaneous preparations of Ig are also now available. Each preparation is slightly different and has theoretic advantages and disadvantages and specific licensed indications. Ideally, IVIg should contain each IgG subclass; retain Fc receptor activity; have a normal half-life; demonstrate virus neutralization, opsonization, and intracellular killing; and have antibacterial capsular polysaccharide antibody. Furthermore, vasoactive impurities should be absent, and no transmissible infectious agents should be present. The uses of IVIg have been extensively reviewed and the number of theoretical and accepted uses for IVIg is rapidly expanding.

Indications IVIg is indicated for replacement of Igs or for its immunomodulatory effects. Currently, there are six FDA approved indications for IVIg treatment: primary immunodeficiency, pediatric HIV infections, secondary immunodeficiency in chronic lymphocytic leukemia (CLL), idiopathic thrombocytopenic purpura (ITP), Kawasaki disease, and allogeneic stem cell transplantation in patients older than 20 years of age. Some of the FDA indications are no longer applicable, such as in patients with CLL and HIV, given better medications. IVIg is also considered first-line therapy for multiple other conditions, such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), neonatal alloimmune thrombocytopenia (NAIT), posttransfusion purpura (PTP), myasthenia gravis and stiff-person syndrome (Table 115.4). An exhaustive review of all the known established and investigational uses for IVIg cannot be

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reasonably summarized in this chapter. For further information, some excellent reviews are cited in the reference section. A brief summary of some of the more well-established uses of IVIg are presented in the following section.

Primary Immunodeficiency Syndromes Primary congenital immunodeficiency syndromes have been treated with intramuscular Ig for the past 30 years. The use of intramuscular Ig has certain disadvantages: delayed absorption, delivery of inadequate amounts because of small muscle mass, and pain at the injection site. IVIg overcomes these disadvantages, and used prophylactically in patients with primary immunodeficiency has been demonstrated to reduce the number of febrile and infectious episodes as well as improve survival rate. IVIg use in IgG subclass deficiencies is also beneficial.

Chronic Lymphocytic Leukemia CLL may be associated with hypogammaglobulinemia and complications of repeated bacterial infections. IVIg decreases the incidence and severity of bacterial infections in CLL patients with hypogammaglobulinemia and has become accepted prophylactic therapy.

Bone Marrow Transplantation The use of prophylactic IVIg or cytomegalovirus (CMV)–IVIg in CMV-negative bone marrow transplant recipients during the first 100 days posttransplant has been demonstrated to reduce the incidence of symptomatic CMV-associated disease, including CMV interstitial pneumonia, in some trials. Because of the high cost of this treatment and the increasing use of prophylactic ganciclovir, IVIg is currently not indicated for the prophylaxis of CMV infections in bone marrow transplant recipients. In established CMV-interstitial pneumonia, IVIg in combination with ganciclovir has been shown to reduce the mortality rate and has become the recommended treatment modality. Its role in preventing severe graft-versus-host disease is unclear. Prolonged IVIg therapy during graft-versus-host disease prevention may suppress humoral immunity recovery.

Pediatric Human Immunodeficiency Virus Infection The defects in humoral and cellular immunity observed in children with HIV infection predispose them to life-threatening bacterial infections. Studies previously demonstrated that the administration of IVIg to HIV-infected children could reduce the incidence and severity of bacterial infections as well as the frequency of hospitalization. More recently, studies have now shown that IVIg does not improve outcome, likely because of improved medications for HIV and HIV-associated infections.

Idiopathic Thrombocytopenic Purpura IVIg and Rh immune globulin are routinely and effectively used in the treatment of acute and chronic ITP. IVIg significantly raises the platelet count within 5 days in adults with chronic ITP and in children with acute ITP. The mechanism of action of IVIg in ITP is unknown; one postulation is Fc receptor blockade decreases the removal of antibody-coated platelets. Other proposed mechanisms include suppressed antiplatelet antibody synthesis, increased antiviral immunity, and blockage by antiidiotypic antibodies. In general, IVIg induces responses in most patients within 1 to 2 days. Responses are of variable duration and are rarely sustained, although maintenance therapy may be of some value. IVIg may be effective in chronic ITP refractory to corticosteroids or splenectomy; and may show greater efficacy in conjunction with corticosteroids.

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Administration of Intravenous Immunoglobulins

Indicated Ataxia-telangiectasia Chronic inflammatory demyelinating polyneuropathy Chronic lymphocytic leukemia Common variable immunodeficiency Cytomegalovirus-interstitial pneumonia after bone marrow transplantation Guillain–Barré syndrome Graft-versus-host disease after bone marrow transplantation Hemolytic disease of the fetus and newborn Idiopathic thrombocytopenic purpura Immunoglobulin G subclass deficiency Inflammatory myopathies (refractory dermatomyositis and polymyositis) Myasthenia gravis Mucocutaneous lymph node syndrome (Kawasaki disease) Neonatal alloimmune thrombocytopenia Parvovirus infection Pediatric human immunodeficiency virus infection Persistent deficit in antibody production after bone marrow transplantation Posttransfusion purpura Primary immunodeficiency syndromes Secondary hypogammaglobulinemia Severe combined immunodeficiency Stiff-person syndrome Wiskott-Aldrich syndrome X-linked agammaglobulinemia Possibly Indicated Antiphospholipid syndrome in pregnancy Autoimmune hemolytic anemia (warm type unresponsive to prednisone) Factor VIII inhibitors (refractory) Graves ophthalmopathy Immune neutropenia Multiple myeloma (stable disease, high risk for infections) Pemphigus

Although IVIg has shown equal efficacy with corticosteroids in pediatric acute ITP and in 75% of adults with chronic ITP, because of the transient responses and high cost, its use is justified only in clinical situations requiring rapid elevation of platelet count or if standard therapy has failed. IVIg is, therefore, indicated in acute bleeding episodes or before urgent surgery, including splenectomy; in patients at high risk of intracranial hemorrhage; and in those in whom corticosteroids are contraindicated or ineffective. IVIg has also been used to treat ITP during pregnancy, postinfectious thrombocytopenia, ITP associated with HIV infection, and neonatal thrombocytopenia. Intravenous anti-D immune globulin (also known as Rh immune globulin) has demonstrated efficacy in Rh-positive, nonsplenectomized individuals with ITP. It has been suggested that the mechanism of action may involve a shift in the immune-mediated destruction from platelets to the antibody-coated RBCs (Chapter 131).

Kawasaki Disease The mucocutaneous lymph node syndrome (Kawasaki disease) has been treated with aspirin with or without concomitant IVIg administration. Coronary artery aneurysm, a serious complication of this disease, was significantly reduced in the IVIg-treated group. However, in a multicenter retrospective survey of all children treated with Kawasaki disease, persistent or recrudescent fever after their first course of IVIg was associated with a statistically significant risk of treatment failure. Furthermore, IVIg retreatment in those patients with persistent fever after IVIg treatment failure was approximately 60%. Current randomized trials are now being done to compare the efficacy of newer, and perhaps better, therapies, such as infliximab (anti-tumor necrosis factor α). To date, these randomized control

Solid organ transplantation (kidney) Systemic lupus erythematosus (refractory, severe, active) Thrombocytopenia refractory to platelet transfusion Vasculitis (refractory to standard therapy) Investigational Acquired von Willebrand disease Amyotrophic lateral sclerosis Burn patients Chronic fatigue syndrome Chronic human parvovirus B19 infection Chronic idiopathic pericarditis Chronic pain syndromes Congestive heart failure Dilated cardiomyopathy Graft-versus-host disease Human immunodeficiency virus infection Immune-mediated aplastic anemia Inflammatory bowel disease Intractable childhood epilepsy Multiple sclerosis Myocarditis Necrotizing fasciitis Neonatal sepsis Neonatal hemochromatosis Postpartum cardiomyopathy Prevention of nosocomial postoperative infections Prophylaxis in transplant recipients against cytomegalovirus infection Recurrent unexplained spontaneous abortions Rheumatoid arthritis Sepsis and septic shock Toxic epidermal necrolysis/Stevens-Johnson syndrome Toxic shock syndrome

studies show that infliximab is at least as safe and as efficacious as IVIg in these refractory patients. One retrospective review has even suggested that infliximab might result in faster resolution of fever and fewer days of hospitalization in comparison with IVIg. While studies are still ongoing, IVIg may soon be replaced by alternative therapies in this refractory patient population. With regard to the pathogenesis of Kawasaki disease, decreased peripheral blood lymphocyte apoptosis has been demonstrated. Therefore, the effect of IVIg in Kawasaki disease has been postulated to partially reverse inhibited lymphocyte apoptosis.

Solid Organ Transplantation The presence of high-titer reactive antibodies against incompatible graft HLA or ABO antigens increases the risk of early solid organ, antibody-mediated, graft rejection and mortality, especially in kidney and cardiac transplants. For some patients who have HLA antibodies to undergo transplantation, these antibodies must be removed or decreased. While morbidity and mortality can be reduced by selecting an adequately cross-matched donor, IVIg with or without plasma exchange has also been shown to decrease sensitization of incompatible antigens in patients awaiting renal and cardiac transplantations. In addition, IVIg with or without plasma exchange is used in the treatment of biopsy-proven antibody-mediated rejection. One review discussed three randomized control trials which investigated the use of IVIg for renal transplantation and revealed a trend in improvement in desensitization rates and a statistically significant decrease in time to transplant for patients treated with IVIg, superior graft survival rate in kidney transplant patients desensitized with IVIg, and a lower rate of recurrent acute rejection with IVIg in comparison to OKT3

Chapter 115  Transfusion of Plasma and Plasma Derivatives

(murine monoclonal antibody to CD3 antigen of human T cells). Consequently, current consensus renal transplant guidelines indicate IVIg is a useful treatment modality for desensitization of patients with HLA antibodies and in patients with acute rejection. Randomized trials have not yet been performed for ABO incompatible kidney transplants, heart, liver, or lung transplants. Moreover, there is a paucity of data for transplant outcomes, and current studies have small numbers without data on donor specific antibody levels. Current guidelines assert that there is insufficient evidence to make a recommendation for or against the routine use of IVIg for desensitization in these transplants.

Aplastic Anemia Secondary to Parvovirus Parvovirus B19 infection can result in severe anemia and reticulocytopenia, especially in immunocompromised individuals or individuals with sickle cell disease or thalassemia, and the use of IVIg is considered first-line therapy in the treatment of these patients (typical dose 0.5 g/kg weekly for 4 weeks).

Chronic Inflammatory Demyelinating Polyradiculoneuropathy CIDP is a chronic disorder resulting in demyelination of peripheral nerves that result in weakness and sensory changes. Equivalent outcomes have been observed in the treatment of CIDP with IVIg (reported dose 400 mg/kg/day for 5 days, once each month, or 1 g/kg/day for 2 days, once each month), TPE, or glucocorticosteroids. The decision as to which treatment to use is made on an individual basis balancing the risks and benefits of each treatment modality.

Dermatomyositis Dermatomyositis is a chronic inflammatory disorder that results in progressive weakness and rash. IVIg (typical dose 2.0 g/kg per month administered over 2–5 days) results in improved muscle strength and neuromuscular symptoms.

Guillain-Barré Syndrome (Acute Inflammatory Demyelinating Polyneuropathy) Guillain-Barré syndrome is an acute demyelinating peripheral neuropathy affecting both motor and sensory nerves. IVIg (typical dose 400 mg/kg/day for 5 days or 1.0 g/kg/day for 2 days or 2.0 g/kg as a single dose) is likely equivalent to TPE in improving disability and shortening the time to improvement.

Hypogammaglobulinemia Associated With Multiple Myeloma Multiple myeloma is a monoclonal B-cell (plasma cell) disorder with clinical symptoms arising as a result of plasma cell infiltration of the bone marrow, monoclonal Ig in the blood and urine, and immunosuppression. IVIg has shown to be beneficial in preventing serious infections in plateau-phase multiple myeloma or other hematologic malignancy, where the patients have hypogammaglobinemia, at doses of 0.4 g/kg every 4 weeks, with subsequent dosing adjusted based on trough levels.

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in association with monoclonal Igs. One placebo-controlled trial demonstrated that IVIg may improve short-term morbidity, but the remainder of the available evidence is mixed. The use of IVIg for this condition has recently fallen out of favor with current consensus groups.

Inclusion Body Myositis Inclusion body myositis is an inflammatory myopathy resulting in chronic muscular weakness. Randomized trials using IVIg appear to result in short-term improvement in strength scores and improved swallowing in patients with inclusion body myositis, and are equivalent to treatment with glucocorticosteroids in one small clinical study. The use of IVIg for this condition has also recently fallen out of favor with current consensus groups because of the lack of known sustained benefit for patients with this condition.

Lambert-Eaton Myasthenic Syndrome Lambert-Eaton myasthenic syndrome results from antibodies to the neuromuscular junction, leading to autonomic dysfunction. One randomized control trial reveals that IVIg significantly improves generalized central and peripheral muscle strength and decreases serum calcium channel antibody titers. A total dose of 2.0 g/kg given over 2 to 5 days is a recommended initial treatment.

Multifocal Motor Neuropathy Multifocal motor neuropathy is a chronic progressive disorder resulting in primarily hand weakness. IVIg is now considered a first-line treatment for this condition, and improved strength can be seen at a dose of 2.0 g/kg over 2 to 5 days.

Multiple Sclerosis Multiple sclerosis is a chronic progressive or relapsing and remitting disorder characterized by brain white mater demyelination. There are two published metaanalyses, and several randomized controlled clinical trials in patients with relapsing-remitting multiple sclerosis using a wide range of IVIg doses that demonstrate the success of IVIg in reducing the number of exacerbations and disability in patients with relapsing-remitting multiple sclerosis in comparison with placebo. However, no studies to date have compared IVIg with standard therapies, and one clinical trial (PRIVIG trial) has raised doubt that IVIg is effective as a routine treatment. Consequently, IVIg is considered a viable second-line option for those patients who fail, decline, or are unable to tolerate standard immunomodulatory therapies such as β-interferon and glatiramer acetate.

Myasthenia Gravis Myasthenia gravis is a chronic neurologic autoimmune disorder characterized by weakness and fatigue upon repetitive skeletal muscle use, which improves with rest. IVIg has been used successfully as a short-term measure for acute severe exacerbations of myasthenia gravis at a dose of 2.0 g/kg given over 2 to 5 days, and appears comparable with TPE. A definitive randomized control trial comparing the two treatment modalities has not been done, however.

IgM Paraproteinemic Demyelinating Neuropathy

Neonatal Alloimmune Thrombocytopenia

Paraproteinemic demyelinating neuropathy is a chronic disorder resulting in decreased sensory and motor function, similar to CIDP,

NAIT is a rare condition that results from maternal platelet alloantibodies against the fetal/neonatal platelets resulting in neonatal/fetal

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thrombocytopenia. Studies evaluating the use of IVIg for NAIT are limited, but unlikely to improve because of the rarity of the condition. The treatment of NAIT during pregnancy is maternal administration of 1.0 g/kg IVIg weekly as a first-line therapy beginning at 20 weeks of gestational age with the use of glucocorticosteroids, or 2.0 g/kg weekly if steroids are not used. Once at 32 weeks of gestation, the IVIg dose is increased to 2.0 g/kg weekly with corticosteroids. Moreover, the neonate may need to receive IVIg and platelet transfusions after delivery to increase fetal platelet counts to prevent intracerebral hemorrhage at a dose of 1.0 g/kg (Chapter 131).

Hemolytic Disease of the Fetus and Newborn Hemolytic Disease of the Fetus and Newborn (HDFN) results from maternal RBC alloantibodies binding to fetal/neonatal RBCs and may result in hemolysis, leading to anemia or hydrops fetalis and death depending on the severity. Two metaanalyses reveal that IVIg significantly reduces the need for exchange transfusions in patients with HDFN. IVIg is now consequently recommended at a dose of 0.5 to 1.0 g/kg to treat newborns with HDFN if there is established jaundice and a rising total serum bilirubin despite phototherapy. In addition, maternal IVIg infusion (with or without therapeutic plasma exchange) has been used in severe cases of HDFN where treatment must occur before the ability to perform intrauterine transfusions.

needing protection against infection. Initially, serial IgG level determination may allow the physician to individualize the dose and schedule. These are affected by the recovery, half-life, redistribution, and catabolism of IVIg, which vary from product to product and patient to patient. Patients with ITP are usually initially treated with 400 to 1000 mg/kg daily for 2 to 5 consecutive days with a maximum dose of 2.0 g/kg. Maintenance doses of 400 to 1000 mg/kg/dose every 3 to 6 weeks is recommended in some patients (particularly children) based on clinical response and platelet count. Kawasaki disease is treated with 2.0 g/kg as a single dose in combination with aspirin. Currently, direct comparisons between different IVIg formulations or brands are lacking, and so evidence-based recommendations cannot be made along these lines.

Adverse Effects

PTP is a rare complication of transfusion resulting in acute, profound thrombocytopenia, secondary to platelet antibodies that destroy both transfused and autologous platelets. While the evidence evaluating the effect of IVIg in these patients is limited to multiple case reports, the available evidence suggests that IVIg should be a first-line therapy for this condition. PTP treatment with IVIg at a dose of 2 g/kg over 2 days or 0.4–0.5 g/kg daily for 5 days can result in a rapid increase in platelet count.

Infusions of IVIg should be started slowly and patients should be closely monitored. If the initial rate (0.5 mL/kg/h) is well tolerated, the rate can be increased gradually, but not more than eightfold. That said, initial and maximum infusion rates vary by IVIg product, and product inserts should be consulted prior to selecting an appropriate infusion rate. Fever, headache, nausea, vomiting, fatigue, backache, leg cramps, urticaria, flushing, elevation of blood pressure, and thrombophlebitis may be seen. Adverse events have been reported in 2% to 10% of infusions. IgA-deficient patients may have IgG antiIgA antibodies, which can cause anaphylactic reactions. This complication is rare and may be avoided by using products with a lower concentration of IgA. Aggregated IgG may produce chills, nausea, flushing, chest tightness, and wheezing. Rarely, IVIg preparations contain RBC antibodies that can produce hemolysis or interfere with serologic evaluations, including RBC compatibility testing. IVIg treatment will produce a false positive direct antiglobulin test, and sometimes positive hepatitis and CMV serologies. Serum sickness can also occur. Lastly, high-dose IVIg therapy has been associated with thrombosis, reversible acute renal failure, TRALI, and aseptic meningitis. Improved manufacturing processes currently in place render IVIg free of enveloped and nonenveloped viruses.

Sepsis and Septic Shock in Adults

HYPERIMMUNE IMMUNOGLOBULIN PRODUCTS

The use of IVIg in adult patients with bacterial sepsis or septic shock is potentially beneficial. One randomized control trial reveled that in ICU patients with intraabdominal sepsis and shock, IVIg with antibiotics was superior to antibiotics with albumin in improving patient survival. Encouraging results have also been identified in patients receiving IVIg for streptococcal toxic shock syndrome, but further studies are currently needed.

Hyperimmune globulins are concentrated immune globulins with specificity for an antigen, or group of antigens. These products are manufactured in a similar manner to that used for IVIg product production. However, donors for these specific products are unique in that they have high titers for the Ig specificity of interest. The donor high titers can be achieved via natural immunity, prophylactic immunization, or target immunization, depending on the antibody of interest. These products are generally used to provide passive immunity for a variety of conditions that are described in more detail in the following sections (Table 115.5).

Posttransfusion Purpura

Stiff-Person Syndrome Stiff-person syndrome is a neurologic disorder associated with truncal and limb rigidity and heightened sensitivity. One small randomized control trial suggests that IVIg could play a positive role in improving stiffness and sensitivity symptoms. Currently, IVIg is considered a second-line therapy for those who fail or cannot tolerate GABA (glutamic acid decarboxylase)-ergic medications. A dose of 2.0 g/kg given over 2 to 5 days is the current recommended starting dose.

Dosage The dosage and frequency for IVIg varies significantly depending on the age of the patient and the clinical indication. Many typical dosages were described in the preceding section. In general, patients require 200 to 800 mg/kg intravenously every 3 to 4 weeks to achieve adequate IgG levels if immunodeficient (usually 500 mg/dL) and

TABLE 115.5

Hyperimmune and Intramuscular Immunoglobulins

Antithymocyte globulin Botulism immunoglobulin Cytomegalovirus immunoglobulin Hepatitis A immunoglobulin Hepatitis B immunoglobulin Rabies immunoglobulin Respiratory syncytial virus immunoglobulin Rh(D) immunoglobulin Tetanus immunoglobulin Vaccinia immunoglobulin Varicella-zoster immunoglobulin Western equine encephalitis immunoglobulin

Chapter 115  Transfusion of Plasma and Plasma Derivatives

Antithymocyte Globulin Antithymocyte globulin is a purified concentrated globulin made from hyperimmune serum of horses immunized with human T lymphocytes. Antithymocyte globulin is used in renal transplant patients as an adjunct therapy in the treatment of graft rejection. It is also used in patients with aplastic anemia who are not candidates for bone marrow transplantation.

Hyperimmune Immunoglobulin Hyperimmune globulin is used to prevent the development of specific clinical disease or alter its symptomatology. Hepatitis B Ig is used to provide passive immunity to hepatitis B virus associated with needle stick exposure or sexual contact with hepatitis B surface antigenpositive individuals, postliver transplantation for prevention of recurrence, and prevention of hepatitis B vertical transmission. Other hyperimmunoglobulins include botulism, CMV, hepatitis A, rabies, respiratory syncytial virus, tetanus, vaccinia, and varicella-zoster virus Igs.

Rh Immunoglobulin Rh Ig has two primary indications: prevention of D antigen alloimmunization and treatment of ITP. Rh Ig is given to D-negative mothers after potential exposure to fetal D-positive RBCs, such as after abortion or amniocentesis, as well as at 28-weeks gestational age, and postpartum if the child proves to be D positive. The therapeutic effect is thought to be caused by antibody feedback with T-cell suppression of the B-cell clone responsible for the formation of anti-D antibody. Rh Ig can also be given to prevent immunization in D-negative individuals given D-positive blood products, such as platelets. Rh Ig is dosed to adequately prevent D immunization. In the United States, 300 µg are administered after event resulting in maternal-fetal hemorrhage, 28 weeks and postpartum. Doses are increased for evidence of large maternal-fetal hemorrhage (300 µg for every 15 mL of RBC exposure). This dosing is also used in the prevention of D alloimmunization after receipt of RBC containing blood product. Rh Ig should be given within 72 hours after RBC exposure. Adverse events to low doses, such as those used to prevent D immunization include fever, chills, and pain at the injection site. Rarely, hypersensitivity reactions are noted. See box “Weak, Partial D, and Rh Ig Use” for more information.

Weak, Partial D, and Rh Ig Use Clinically significant D sensitization potentially results in a pregnancy with a fetus at risk for hemolytic disease of the fetus and newborn and hemolytic transfusion reactions if transfused with D-positive red blood cells. In rare cases, as a result of a mutation in the D gene, a person may have amino acid substitutions affecting a part of the normal D protein that changes the antigen on the external aspect of the red cell. These patients are described as having “partial D.” When someone with partial D is exposed to blood from someone with a normal form of D, they may make an antibody against the portions of the D antigen that they lack. Individuals with red blood cells that express a partial D antigen are thus at risk for D-sensitization and may benefit from Rh Ig administration to prevent D sensitization. Mutations which result in fewer “normal” D antigens on a red cell are known as having a “weak” D. Those with weak D antigens are usually not at risk for D sensitization because they have a normal D protein, and thus do not require Rh Ig administration. Partial and weak D antigens cannot be distinguished by serologic reactivity, because either may present as weak, moderately, or strongly positive or give variable results with anti-D reagents. Particularly in the prenatal setting, RhD genotyping can be done to distinguish weak D from partial D to help determine need for Rh Ig administration.

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Rh Ig doses are substantially higher for the treatment of ITP: 50 µg/kg for hemoglobin ≥10 L/dL and 25 to 40 µg/kg when hemoglobin is 8 to 10 g/dL. Rh Ig use in ITP is indicated in D-positive patients with intact spleen. Adverse events at high doses of Rh Ig include hemolysis, DIC, and rarely death (Chapter 131).

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SAFE study investigators: Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med 357:874–884, 2007. Sandler SG: The status of pathogen-reduced plasma. Transfus Apher Sci 43:393–399, 2010. Scott E, Puca K, Heraly J, et al: Evaluation and comparison of coagula­tion factor activity is fresh-frozen plasma and 24-hour plasma at thaw and after 120 hours of 1 to 6°C storage. Transfusion 49:1584–1591, 2009. Shaz BH, Stowell SR, Hillyer CD: Transfusion-related acute lung injury: from bedside to bench and back. Blood 117:1463–1471, 2011. Shehata N, Palda VA, Meyer RM, et al: The use of immunoglobulin therapy for patients undergoing solid organ transplantation: An evidence based practice guideline. Transfus Med Rev 24:S7–S27, 2010. Spotnitz WD, Burks S: Hemostats, sealants, and adhesives II: Update as well as how and when to use the components of the surgical toolbox. Clin Appl Thromb Hemost 16:497, 2010. Stanworth SJ: The evidence-based use of FFP and cryoprecipitate for abnormalities of coagulation tests and clinical coagulopathy. Hematology 179–186, 2007.

Stanworth SJ, Brunskill S, Hyde CJ, et al: What is the evidence base for the clinical use of FFP: a systematic review of randomized controlled trials. Br J Haematol 126:139–152, 2004. Schwartz J, Padmanbhan A, Aqui N, et al: Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the writing committee of the American Society for Apheresis: the Seventh Special Issue. J Clin Apher 31:149–162, 2016. Theusinger OM, Goslings D, Studt JD, et al: Quarantine versus pathogenreduced plasma-coagulation factor content and rotational thromboelastometry coagulation. Transfusion 2016 Epub. Triulzi D, Gottschall J, Murphy E, et al; NHLBI Recipient Epidemiology and Donor Evaluation Study-III (REDS-III): A multicenter study of plasma use in the United States. Transfusion 2014. doi:10.1111/trf.12970. [Epub ahead of print]. Zielinski MD, Johnson PM, Jenkins D, et al: Emergency use of prethawed Group A plasma in trauma patients. J Trauma Acute Care Surg 74(1):69–74, 2013.