Category Storage Shelf Life Additional Criteria

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1 CE Update [blood banking/transfusion medicine] Blood Components for Hemostasis Jun Teruya, MD, DSc, and Glenn Ramsey, MD From the Department of Pathology, Northwestern University Medical School, Chicago. On completion of this article, the reader will be able to describe the clinical indications and dosages for transfusing platelets, plasma, and cryoprecipitate. Blood banking/transfusion medicine exam 0102 questions and the corresponding answer form are located after the Your Lab Focus section. Transfusion of platelets, plasma, or cryoprecipitate Use of plasma to provide clotting factors Plasma products used to treat thrombotic thrombocytopenic purpura Blood Components for Hemostasis* The guiding principle of blood component therapy is to provide the specific product needed by each patient. Platelets, plasma, and cryoprecipitate each have different indications for various types of coagulopathies. The clinical condition, the presence of bleeding or an invasive procedure, the platelet count, and coagulation testing are all factors in determining which hemostatic blood components to transfuse. Table 1 [T1] lists the blood components used for hemostasis. Category Storage Shelf Life Additional Criteria T1 Platelets 20 C-24 C with continuous gentle agitation 5 d Maximum time without agitation 24 h Platelet pooled or open system 20 C-24 C with continuous gentle agitation 4 h, unless otherwise specified Platelets, pheresis 20 C-24 C with continuous gentle agitation 5 d Maximum time without agitation 24 h FFP 18 C or less 12 mo Frozen within 8 h of collection in CPD, CP2D, CPDA-1 65 C or less 7 y Frozen within 6 h of collection in ACD FFP thawed 1 C-6 C 24 h Thaw at 30 C-37 C or FDAapproved microwave device Thawed plasma 1 C-6 C More than 24 h, less than 5 d Closed system Liquid plasma 1 C-6 C 5 d after expiration of RBCs Plasma frozen within 24 h 18 C or less 12 mo Solvent/detergent-treated 18 C or less 12 mo from manufacture; pooled plasma manufacturer states expiration date on label Solvent/detergent-treated 20 C -24 C 24 h pooled plasma, thawed Cryoprecipitated AHF 18 C or less 12 mo Thaw FFP at 1 C-6 C, refreeze cryoprecipitate within 1 h Cryoprecipitated AHF, thawed 20 C-24 C Open system or pooled: as soon as possible or 4 h Single unit or pooled prior to freezing: 6 h Plasma, cryoprecipitate 18 C or less 12 mo reduced Plasma cryoprecipitate 1-6 C 24 h reduced, thawed 31 ACD, acid citrate dextrose; AHF, antihemophilic factor; CP2D, citriate phosphate 2-dextrose; CPD, citrate phosphate dextrose; CPDA-1, CPD adenine; FDA, US Food and Drug Administration; FFP, fresh-frozen plasma. *From American Association of Blood Banks Standards for Blood Banks and Transfusion Services. 1 Plasma separated from the blood of an individual donor. FFP from which cryoprecipitate has been removed

2 32 your lab focus Platelet Transfusion Product Options Platelets are transfused either as random-donor platelets from whole-blood donations or as plateletpheresis units collected by apheresis. Random-donor units are somewhat less expensive per dose, but compared with plateletpheresis units they expose the recipient to more donors, are more prone to bacterial contamination, and are more cumbersome to reduce the number of leukocytes before storage. Plateletpheresis units are commonly produced with reduction of leukocytes techniques and are convenient to issue without pooling. The possibility of bacterial contamination and growth at the room temperature of platelet storage currently limits the shelf life of platelets to 5 days. If bacteria can be prevented or destroyed through sterilization in the future, platelet additives may be able to significantly extend the storage period [T1]. Platelet transfusions are administered when hemostasis is needed in the settings of thrombocytopenia or platelet dysfunction. 2 The risk of bleeding from a profoundly low platelet count has been reassessed in recent years [T2]. Formerly, platelet counts less than /µl ( /L) were thought to cause spontaneous hemorrhage. However, recent studies have revised this threshold. Serious bleeding does not usually occur until the patient s platelet count is less than /µl ( /L); therefore, prophylactic platelet transfusions are recommended for severe thrombocytopenia to this degree. Patients with platelet counts between 10 and /µl (10 and /L) may also be at risk if they have conditions causing increased platelet turnover, such as high fever or severe infection. For patients who are bleeding or who have an impending invasive procedure, a platelet count of more than /µl ( /L) is usually sought. For bleeding in critical anatomic sites such as the central nervous system or the airway, higher platelet counts may be needed. Patients receiving large amounts of RBCs and other fluids may develop dilutional thrombocytopenia after more than 1 blood volume of transfusions. Thrombocytopenia and Bleeding Risks Platelet Count Platelet dysfunction in the setting of bleeding or invasive procedures often requires treatment. Common causes of platelet dysfunction include antiplatelet medications, uremia, and cardiopulmonary bypass. Assessment of platelet dysfunction can be difficult. The bleeding-time test is a poor predictor of bleeding risk. Newer in vitro measurements of platelet activity are under investigation to augment the traditional clinical picture of systemic microvascular bleeding. 3 The first line of treatment is usually the drug desmopressin acetate (DDAVP), which may improve platelet function by stimulating the release of von Willebrand factor (vwf) into the blood from endothelial cells. However, if this does not control bleeding sufficiently, platelet transfusions may be needed. Platelet transfusions are usually avoided in patients with thrombotic thrombocytopenic purpura (TTP) because they may worsen the condition. In immune thrombocytopenic purpura, platelet transfusions are usually given only in bleeding emergencies because the autoantibodies promptly remove the transfused platelets from the circulation. The typical platelet dose for adults is 1 standard plateletpheresis unit or its equivalent of approximately 5 to 6 random-donor units. The minimum required content of these units is platelets, but about platelets are usually provided. This should be enough to increase the averagesized adult s platelet count by 30 to /µl (30 to /L), in the absence of refractoriness. Small children are given 1 random-donor unit per 10 to 15 kg Risk of Bleeding /µl or more ( /L or more) Bleeding with surgery, trauma, and invasive procedures unlikely /µl ( /L) Spontaneous bleeding unlikely; bleeding likely with surgery, trauma, and invasive procedures /µl ( /L) Risk of spontaneous bleeding < /µl (< /L) High risk of spontaneous bleeding T2 of body weight. Patients who need recurrent platelet transfusions should receive leukocyte-reduced RBCs and platelets to reduce their risk of HLA alloimmunization. A debate has emerged recently about the merits of higher or lower doses of platelets. In many plateletpheresis donations, a higher platelet content, or even 2 minimum-content products, can be obtained. Transfusions averaging platelets have been investigated as a way to increase platelet counts or to maintain the increase over a longer period of time. 4 On the other hand, the concept of more frequent transfusions with smaller amounts of platelets, such as 3 randomdonor units, has been proposed to reduce total platelet requirements while maintaining hemostatic platelet levels. 5 Further studies of this issue are anticipated. Physicians usually attempt to achieve a threshold platelet count; refractoriness is defined in terms of the percentage of the predicted platelet increment achieved for a given platelet content and body size. The platelet response is best assessed within 15 to 60 minutes after the transfusion. The patient s response is considered refractory when each of at least 2 transfusions fails to achieve one third to one half of the expected increment. For a 70-kg patient receiving a dose of platelets, this would be an increment of less than /µl ( /L). Refractoriness has many causes: active bleeding, splenomegaly, severe infection or fever, disseminated intravascular coagulation, platelet autoantibodies, and drug antibodies. ABO-incompatible platelet transfusions average about two thirds of the regular platelet count rise and, in some patients, yield poor responses

3 because of high anti-a/b levels. Plateletspecific antibodies develop in a small number of patients. However, immune refractoriness is often due to HLA antibodies. Diagnosis is made by HLA antibody testing. In alloimmunized patients, platelet crossmatching or HLA-matched platelets may improve transfusion responses. Plasma Transfusion Product Options Fresh frozen plasma (FFP) is prepared by centrifugation within 8 hours of whole blood collection in citrate phosphate dextrose adenine, citrate phosphate dextrose, and citrate phosphate 2-dextrose and 6 hours in acid citrate dextrose. It is stored at 18 C or less for up to 12 months. It should be thawed at 30 C to 37 C and can be used as FFP for up to 24 hours after thawing. FFP contains all the proteins including labile coagulation factors at the same level as they circulate in vivo. Twenty-four hours after thawing, it can be used as thawed plasma, which contains a somewhat reduced amount of labile factor V and factor VIII, for 5 days after thawing. Liquid plasma is prepared by centrifuge of a whole blood unit at any time and stored at 1 C to 6 C until use. Liquid plasma contains a reduced amount of labile coagulation factor V and factor VIII. According to National Institutes of Health guidelines published in 1993, FFP should be administered only to increase the level of clotting factors in patients with a demonstrated deficiency [T3]. 6 Deficiency of coagulation factors can be measured by prothrombin time (PT) and activated partial thromboplastin time (aptt) for extrinsic pathway and intrinsic pathway, respectively. Patients with TTP may benefit from FFP transfusion. Especially for patients with idiopathic TTP, who are considered to have autoantibody against the cleavage enzyme of unusually large vwf, plasma exchange with FFP is the only efficacious treatment. Clinicians should not transfuse FFP for volume expansion, as a nutritional supplement, or prophylactically with massive blood transfusion and following cardiopulmonary bypass. Factor-specific concentrates or recombinant factors are marketed for factor VII, VIII, or IX deficiencies. In the United States, antithrombin concentrate and alpha 1 - antitrypsin are approved for their respective congenital deficiencies. FFP should not be used if a specific coagulation factor or protein is available since the latter is sterilized. Unless the PT or aptt exceeds 1.5 to 1.8 times control values, FFP is rarely indicated since clinically significant bleeding is not common. However, because factor sensitivity of PT and aptt reagents varies between manufacturers, there is no definite threshold. For example, when the factor XI level is 10% of normal, the aptt in use at our institution (reference range, seconds) is 34.2 seconds. Because a 30% level of factor XI is usually needed to obtain hemostasis during surgery, a normal aptt does not always guarantee that the factor XI is sufficient. One unit of FFP is usually 200 to 250 ml. The FFP transfusion must be ABOcompatible [T4]. It can be given without regard to Rh type, and crossmatching is not required. The following formula is used to calculate dosage for specific factor replacement in adults: Body Weight (kg) 70 ml/kg = Total Blood Volume (ml) Total Blood Volume (ml) (100 Hematocrit)/100 = Total Plasma Volume (ml) for Plasma Transfusion Indication Coagulation Factor or Protein Deficiency Comments T3 Replacement of single factor Factors V, X, and XI, protein C, and protein S Factors VIIa, VIII, IX, antithrombin, and alpha 1 - deficiencies in which a specific factor antitrypsin concentrates are on market concentrate is unavailable Immediate reversal of warfarin effect Factors II, VII, IX, and X, protein C and protein S If the patient can wait 10 h, administer parenteral vitamin K Vitamin K deficiency associated with Factors II, VII, IX, and X, protein C and protein S It is commonly associated with a prolonged use of active bleeding antibiotics Acute disseminated intravascular All coagulation factors, protein C, protein S, coagulation and antithrombin Liver disease All coagulation factors (except factor VIII), The goal should be to correct or prevent bleeding protein C, protein S, and antithrombin complications, not to achieve a normal prothrombin time Dilutional coagulopathy All coagulation factors and proteins It is seen in massive transfusion of more than 1 blood volume and intensive daily pheresis with 5% albumin Thrombotic thrombocytopenic Congenital deficiency of von Willebrand factor Usually used as replacement fluid for plasma purpura/hemolytic uremic syndrome cleavage enzyme or autoantibody to the enzyme exchange 33

4 Total Plasma Volume (ml) (Desired Level Patient Level) U/mL = Needed Factor Level (U) (1 U/mL is 100%) For example, if a 100-kg patient, who is known to hemorrhage, with low factor XI of 5% is going to surgery and needs a 50% level, it is calculated as follows: 100 kg 70 ml/kg = 7,000 ml 7,000 ml (100 40)/100 = 4,200 ml 4,200 ml ( ) U/mL = 1,890 U Assuming 1 U of FFP contains 1 U/mL (100%) of factor XI, 1,890 U/1 U/mL = 1,890 ml Assuming 1 U of FFP is 250 ml, 1,890 ml/250 ml = 7.56 U Patient and Plasma ABO Types Recipient ABO First Choice Second Choice O O A, B, AB A A AB B B AB AB AB None Biologic Data for Coagulation Factors and Inhibitors Coagulation Factors Biological Half-Life Levels to Achieve and Inhibitors for Hemostasis Fibrinogen 3-4 d 100 mg/dl (1.0 g/l) T4 T5 34 Therefore, 8 U of FFP should be given usually every 24 hours. Table 5 [T5] shows the biological half-lives and hemostatic levels for each major coagulation factor and inhibitor. Cryoprecipitated Antihemophilic Factor (CRYO) CRYO contains factor VIII, fibrinogen, fibronectin, vwf, and factor XIII in 8 to 15 ml made from the FFP of 1 whole-blood donation. CRYO is recommended for hypofibrinogenemia with bleeding, von Willebrand disease, and hemophilia A when factor VIII concentrate is not available. 7 For mild type 1 von Willebrand disease, DDAVP is a preferred choice of treatment. Because some sterile factor VIII concentrates such as Humate-P (Centeon [M]) contain a significant amount of vwf, CRYO is not widely used to treat von Willebrand disease. A lyophilized vwf product may be on the market soon. Coagulopathy associated with uremia can be treated with CRYO, but DDAVP is usually the first-line therapy. One or 2 U of CRYO is also used for fibrin glue or fibrin sealant during surgery. CRYO and thrombin are applied to the bleeding surface simultaneously, where fibrinogen is converted to fibrin by the action of thrombin. To avoid potential donor exposures, the patient s own CRYO can be harvested for this Factor II 2-5 d 40%-50% of normal ( ) Factor V h 10%-30% ( ) Factor VII 4-7 h 10%-20% ( ) Factor VIII 9-18 h 30%-100% ( ) Factor IX h 20%-60% ( ) Factor X h 10%-40% ( ) Factor XI h 20%-30% ( ) Factor XIII 12 d 10% (0.10) Von Willebrand factor h 20%-50% Protein C 3-5 h 60% Protein S 42 h 60% Antithrombin h 60% use. Virally inactivated fibrinogen concentrate also has been licensed recently for this purpose. One unit contains an average of 250 mg of fibrinogen, with a minimum fibrinogen content of 150 mg, according to the standards of the American Association of Blood Banks. 1 When the patient s fibrinogen level is below 80 to 100 mg/dl (0.8 to 1.0 g/l), CRYO transfusion is usually indicated. One unit of CRYO per 10 kg body weight usually increases plasma fibrinogen level by 50 mg/dl (0.5 g/l) in the absence of continued consumption or massive bleeding. Although 6 to 8 U of CRYO constitute a typical adult transfusion dose, a larger dose of CRYO may be needed for patients with active disseminated intravascular coagulation and increased fibrinolytic activity. One unit of CRYO should contain a minimum factor VIII content of 80 U but is no longer used as a primary source of factor VIII since sterile factor VIII, both concentrate and recombinant, is available. Cryoprecipitate-Reduced Plasma The plasma recovered after removal of cryoprecipitate is the preferred replacement component for plasma exchange for TTP, since it contains far less vwf than plasma. In these conditions, deficiency of a vwf cleavage enzyme leads to the accumulation of large vwf multimers, which causes platelet activation and aggregation. When cryoprecipitate-reduced plasma is used as the replacement fluid in intensive plasma exchange, monitoring the aptt is required since it contains little factor VIII.

5 Conclusions Each blood component should be transfused based on clinical symptoms and laboratory test results. Surgical bleeding can be corrected without giving blood components. To avoid unnecessary transfusion, rapid turnaround time and accurate results for PT, aptt, fibrinogen, and platelet count are necessary. If platelet function can be measured within a reasonable time, unnecessary platelet transfusion for suspected platelet dysfunction can be avoided. It is suggested that clinicians, the blood bank, and the hematology-coagulation laboratory communicate with each other. Such communication can reduce unnecessary blood transfusion and wastage of blood components. 1. Standards for Blood Banks and Transfusion Services. 19th ed. Bethesda, MD: American Association of Blood Banks; Herman JH. Platelet transfusion therapy. In: Mintz PD, ed. Transfusion Therapy: Clinical Principles and Practice. Bethesda, MD: AABB Press;1999: Francis J, Francis D, Larson L, et al. Can the platelet function analyzer (PFA)-100 test substitute for the template bleeding time in routine clinical practice? Platelets. 1999;10: Klumpp TR, Herman JH, Gaughan JP, et al. Clinical consequences of alterations in platelet transfusion dose: a prospective, randomized, double-blind trial. Transfusion. 1999;39: Hersh JK, Hom EG, Brecher ME. Mathematical modeling of platelet survival with implications for optimal practice in the chronically platelet transfusion dependent patient. Transfusion. 1998;38: National Institutes of Health. Transfusion Alert: for the Use of Red Blood Cells, Platelets, and Fresh Frozen Plasma. Bethesda, MD: National Institutes of Health; August NIH Publication a. 7. College of American Pathologists. Practice parameter for the use of fresh-frozen plasma, cryoprecipitate, and platelets. JAMA. 1994;271: